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Enzyme kinetics in drug metabolism: fundamentals and applications

Affiliation.

1 Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
PMID: 24523105
DOI: 10.1007/978-1-62703-758-7_1

Enzymes are protein catalysts that lower the energy barrier for a reaction and speed the rate of a chemical change. The kinetics of reactions catalyzed by enzymes, as well as several mechanisms underlying the kinetics, have been comprehensively studied and written in textbooks (1, 2). The importance of quantitative evaluation of enzymatic processes has been recognized in many fields of study, including biochemistry, molecular biology, and pharmaceutical sciences to name a few. In pharmaceutical sciences, the applications of enzyme kinetics range from hit finding efforts for new chemical entities on a pharmacological target to concentration effect relationships to large-scale biosynthesis. The study of the science of drug metabolism has two principal concepts-rate and extent. While understanding disposition pathways and identification of metabolites provides an insight into the extent of metabolism, kinetics of depletion of substrates (endogenous or exogenous) and formation of metabolites deals with the rate of metabolism. The current textbook specifically focuses on kinetics of drug-metabolizing enzymes, detailing specific enzyme classes, and discusses kinetics as they apply to drug transporters. This textbook also outlines additional factors that contribute to the kinetics of reactions catalyzed by these proteins such as variability in isoforms (pharmacogenomics) and experimental factors including key concepts such as alterations of substrate concentrations due to binding. Applications of these approaches in predicting kinetic parameters and alternative approaches for enzymes (systems biology) and transporters are also discussed. The final section focuses on real-life examples (case studies) to try and exemplify the applications of enzyme kinetic principles. This chapter provides a brief overview outlining some key concepts within each of the sections and the chapters within this textbook.

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Pharmacology and Drug Metabolism

A section of Metabolites (ISSN 2218-1989).

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This section of Metabolites is focused on the change in and/or occurrence of small molecule metabolites in in vitro and in vivo systems triggered by drugs and other xenobiotics. This ranges from classic metabolism studied in new compounds to new and emerging tools as well as toxicometabolomics studies, which investigate the fate of the foreign compounds as well as changes in endogenous molecules.

The section “Pharmacology and Drug Metabolism“ in Metabolites is focused on but not limited to:

Toxicometabolomics (e.g., metabolism of xenobiotics besides answering related metabolomics questions);
Biomarkers of xenobiotics exposure (e.g., metabolomics to allow for tracing an intake);
Detailed characterization of xenobiotics metabolism in biofluids and tissues;
Effect of endogenous microorganisms on biotransformation (e.g., influence of human microbiome on drug metabolism;
Fate of xenobiotics in wastewater (e.g., impact of microorganisms on survival rate);
Emerging tools in metabolomics and applied mass spectrometry (e.g., in drug metabolism);
Drug–drug interactions or drug–food interactions on the metabolism of drugs and, in consequence, on therapeutic management;
Adverse drug reactions in polypharmacy patients and related management (e.g., PGx-based guiding);
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Metabolism and toxicity of compounds released from packaging materials (toxicokinetics and biomonitoring).

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DOI: 10.69613/8tckqp18
Corpus ID: 271849441

Evaluating the Impact of AI and ML on Modern Drug Discovery

Nvvs Vinayak , Lingolu , +1 author Pavan Kumar
Published in Journal of Pharma Insights… 4 August 2024
Medicine, Computer Science
Journal of Pharma Insights and Research

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41 References

Nanorobotics: pioneering drug delivery and development in pharmaceuticals, ai-driven natural language processing in healthcare: transforming patient-provider communication, generative adversarial networks for de novo molecular design, artificial intelligence in drug discovery: recent advances and future perspectives, artificial intelligence in drug discovery: what is realistic, what are illusions part 1: ways to make an impact, and why we are not there yet., a deep learning approach to antibiotic discovery, the power of deep learning to ligand-based novel drug discovery, improved protein structure prediction using potentials from deep learning, rethinking drug design in the artificial intelligence era, artificial intelligence for decision making in the era of big data - evolution, challenges and research agenda, related papers.

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Review Article
Open access
Published: 10 May 2023

Signaling pathways in cancer metabolism: mechanisms and therapeutic targets

Mengshu You 1 , 2 , 3 na1 ,
Zhuolin Xie 1 , 2 , 3 na1 ,
Nan Zhang 1 , 2 , 3 na1 ,
Yixuan Zhang 1 , 2 , 3 ,
Desheng Xiao ORCID: orcid.org/0000-0003-2204-5042 4 ,
Shuang Liu ORCID: orcid.org/0000-0002-7206-7277 5 ,
Wei Zhuang 6 ,
Lili Li 7 &
Yongguang Tao ORCID: orcid.org/0000-0003-2354-5321 1 , 2 , 3 , 8

Signal Transduction and Targeted Therapy volume 8 , Article number: 196 ( 2023 ) Cite this article

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Cancer metabolism
Cancer microenvironment

A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.

Cancer metabolism: looking forward

Emerging mechanisms and promising approaches in pancreatic cancer metabolism

To metabolomics and beyond: a technological portfolio to investigate cancer metabolism

Introduction.

Since Warburg discovered aerobic glycolysis as a metabolic marker of cancer cells, extensive studies have enhanced our understanding of the metabolic changes in cancer cells. 1 , 2 , 3 , 4 , 5 Metabolic reprogramming is a common feature of many tumors, enabling cancer cells to meet their specific growth requirements through alterations in glucose, lipid, and amino acid metabolism. 6 , 7 In addition to the well-known phenomenon of aerobic glycolysis, cancer-specific metabolic changes have been discovered, including elevated lactate production, increased glutamine metabolism, fatty acid synthesis, and decreased fatty acid oxidation. 1 , 2 The cellular metabolism of tumors is a complex and diverse spectrum, with each nutrient’s source and metabolic pathways being better understood. 8

Metabolic reprogramming satisfies the growing demands of cancer cells and governs their behaviors by modulating the types and concentrations of metabolites in the tumor microenvironment. 9 In addition to endogenous metabolites, exogenous nutrients also impact the metabolic microenvironment of tumors. Cells possess the ability to sense changes in metabolism and initiate a cascade of reactions known as metabolite sensing, which involves the regulation of cell signaling transductions and epigenetic modifications. 7 Metabolite sensing enables changes in metabolites to be translated into biochemical signals that regulate a series of signal transduction pathways and gene expression in cells. Metabolite sensing serves as a crucial link between the external environment and cells, allowing cells to promptly detect changes in the external environment, reorganize the metabolic network, and adjust cell signaling and other cellular processes. 10 However, some of these changes may promote cancer progression. 11

Metabolite sensing can be achieved in three ways: metabolite sensor-mediated signal transduction, a metabolic sensing module, and conjugate sensing. Metabolite sensors are biological macromolecules, including proteins, RNAs, and DNAs, that directly bind to metabolites, triggering changes in downstream proteins. These sensors possess three key characteristics: 1. Specificity: Specificity is achieved using specific domains that enable sensors to recognize and bind to metabolites with high specificity, ensuring accurate metabolite sensing. 12 2. Dynamicity: Dynamicity refers to the reversible nature of the sensor-metabolite interaction, allowing sensors to sense fluctuations in metabolite concentrations and enabling competitive metabolite binding assays to verify sensor identity. 13 , 14 3. Functionality: Functionality is achieved by changes in the activity or function of metabolic receptors sensors, as the different states of metabolites alter protein conformation or interaction. It is worth noting that the role of receptor sensors is to translate the chemical signal of metabolites into a biological signal that interacts with the biological networks, thereby acting as translators of the cellular environment.

Epigenetic modifications are important in many diseases, especially in cancer development. 15 Epigenetics regulates gene expression without altering the DNA sequence and occur at multiple levels, including chromatin remodeling, DNA modification, histone protein modification, non-coding RNA regulation, and nucleosome positioning. 16 Epigenetic alterations related to oncogenes and tumor suppressor genes often cause cell transformation, tumor progression, and metastasis. 17 For instance, lymphoid-specific helicase (LSH), a chromatin remodeling factor that regulates DNA methylation patterns, has been found to play a crucial role in epigenetics. 11 , 18 LSH is highly expressed in almost all B-cell lymphoma samples 19 and has been implicated in the pathogenesis of other tumors, such as glioma, lung cancer, and nasopharyngeal carcinoma. 20 Metabolites also contribute to chromatin dynamics through chemical posttranslational modifications (PTMs) that alter chromatin structures and functions, in addition to acting as signaling molecules to respond to the environment via metabolite sensing mechanisms. 21 Histones can undergo a wide range of PTMs, such as acetylation, methylation, phosphorylation, and other acylation modifications, as DNA and RNA are chemically modified by methylation. In general, cancer cell proliferation and distant metastasis are related to epigenetic changes, including increased histone acetylation and decreased histone methylation, 22 while DNA methylation is linked to gene silence, 23 histone acetylation is related to gene transcription. 24 Currently, there are two main viewpoints regarding the role of metabolites in epigenetic regulation: one suggests that metabolites provide substrates for epigenetic enzymes, while the other proposes that metabolites act as allosteric regulators of these enzymes. For example, in HeLa cells, acetic acid absorbed from the culture medium can be covalently bound to histones, leading to histone acetylation and the regulation of protein function. 25 This finding supports that metabolites can covalently modify proteins and regulate their functions. In addition, increased succinate inhibits histone demethylase activity, triggering. 26 Recently, epigenetic drugs have received extensive attention, such as histone demethylases (HDM) inhibitors, bromodomain and extra-terminal motif (BET) inhibitors, and histone deacetylase (HDAC) inhibitors. However, these drugs have been ineffective on solid tumors due to stability and dose limitations. As a result, combination therapy has emerged as a promising avenue in epigenetic therapy, with ongoing clinical trials exploring the use of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) mAbs in combination with DNA methyltransferase (DNMT), HDAC and enhancer of enhancer of zest homolog 2 (EZH2) inhibitors are in clinical trials.

In humans, cell metabolism is integrated into a complex biological network that involves a wide range of metabolites and ubiquitous metabolite-sensing mechanisms. Endogenous or exogenous metabolites can regulate signal transduction and epigenetics of these mechanisms. However, aberrant metabolic reprogramming in cancers can lead to abnormal inhibition and activation of metabolite sensing, which is a significant contributor to cancer progression. Thus, the abnormality of metabolite sensing suggests the existence of numerous potential targets that could be targeted to suppress tumorigenesis and cancer development. 27 Meanwhile, epigenetic regulation in cancer development is a post-genomic era revolution in cancer genetics, which may provide new targets for cancer therapy. 28 Interestingly, unlike genetic mutations, epigenetic mutations are reversible, which means that the epigenome can be reprogrammed and has high potential as a therapeutic strategy for cancer. 29

In this review, we focus on the effect of the tumor metabolic microenvironment on cancer cells, especially on how metabolites influence signal transduction and epigenetics in cancer cells. A better understanding of the tumor metabolic microenvironment’s effect on cancer cells’ life activities will be performed and some potential therapeutic targets based on the tumor metabolic microenvironment will be discussed.

Signal transduction and epigenetic regulation of glucose metabolism

Signal transduction mediated by gpcrs.

G protein-coupled receptors (GPCRs) constitute the most prominent family of receptors in mammals and are involved in regulating almost all cellular and physiological functions in the body. These receptors have gained attention as targeted drug development candidates due to their high specificity and affinity for ligand binding, accounting for approximately 20% of currently developed drug targets. 30 Once activated by the ligand, GPCR can be coupled to four different heterotrimeric G protein families (Gs, Gi/Go, Gq/G11, and G12/G13) and then act on different effectors, such as downstream enzymes and ion channels. 31 , 32 , 33 Therefore, the modular structure of the signaling system mediated by GPCR and G protein is vital for its role. In GPCRs, there are several receptors worth paying attention to, and the following are related to glucose metabolism:

GPR31 plays an essential role in the immune system and tumor progression

GPR31 is a G protein-coupled receptor that recognizes citric acid cycle intermediates. In addition to its critical role in inflammation, emerging evidence suggests that GPR31 contributes to tumor progression. 34 Recent studies have identified lactic acid and pyruvate as potent inducers of GPR31-mediated dendritic processes of intestinal CX3CR1 + phagocytes, potentially enhancing the immune response. These findings suggest that GPR31 may play a complex role in cancer development and progression and may represent a promising target for anti-tumor therapy. Further research is needed to fully elucidate the mechanisms underlying GPR31’s functions and to explore its therapeutic potential. 35

The connection between SUCNR1 and the cancer metastasis

Succinate receptor 1(SUCNR1), also known as GRP91, is widely expressed in different organs. SUCNR1 is activated by succinate and as an intermediate molecule of the citric acid cycle. Studies have shown that SUNCR1 plays an essential role in tumor metastasis, especially in individuals with succinate dehydrogenase (SDH) germline mutation. Extracellular succinate activated the PI3K-Akt pathway by combining SUCNR1 in tumor cells and upregulating HIF-1α, promoting cancer cell invasion and driving epithelial–mesenchymal. 36 , 37 , 38 In gastric cancer, it was found that succinate could activate it via the SUCNR1-ERK1/2-STAT3-VEGF pathway leading to the angiogenesis. 39 Besides driving cancer cell migration, extracellular succinate significantly impacts macrophages within the tumor microenvironment. Succinate induces polarization of tumor-associated macrophages (TAMs) by activating the SUCNR-1 receptor on macrophage membranes and its downstream PI-3K/Akt-HIF-1α signaling pathway. This succinate-induced macrophage polarization leads to increased cancer cell migration by promoting the secretion of promigratory cytokines, such as interleukin (IL) -6. Moreover, extracellular succinate targets M2 macrophages and activates M2 macrophage gene transcription through SUCNR1. 40 SUCNR1 expression is upregulated in human SDH-mutated tumors and in various prevalent cancers. It may be associated with heightened risks of tumor metastasis and recurrence, making it a potential predictive biomarker for SDH-mutated tumors.

The function of glucose and its metabolites in epigenetics regulation

Ubiquitination and acetylation, and tyrosine phosphorylation of histone h3 induced by glucose.

Histone protein is an important part of epigenetic regulation. It’s also the central component of the nucleosome which is the element responsible for the stable maintenance of repressive chromatin. The nucleosome is composed of histones H2A, H2B, H3, and H4 in an octameric core with a linker histone, H1. 15 Histone H3 ubiquitination markers are essential in transcriptional regulation. H3 ubiquitination is physiologically induced by glucose, and H3 acetylation has also been extensively studied and has been shown to occur at specific lysine residues, including K9, K14, K27, and K56 by selectively recruiting histone acetyltransferases (HAT) general control non-depressible 5 (GCN5). Whole genome chromatin immunoprecipitation and sequencing (ChIP-seq) data set analysis showed that glucose-induced H3 acetylation in a gene-specific manner (approximately 2000 genes) at the transcription start site (TSS). The comprehensive analysis combined with ChIP-seq and gene expression microarray data sets further indicates that these acetylation events at TSS are significantly related to the expression of their target genes, many of which are involved in cancer-related pathways in the neuronally expressed developmentally down-regulated 4 (NEDD4)-dependent manner. Interestingly, H3 ubiquitination and NEDD4, GCN5, and histone H3 are essential regulators of tumor formation. Glucose-induced H3 ubiquitination target genes, such as IL-1α, IL-1β, and glutamate-cysteine ligase modifier (GCLM) subunit, are also important factors for tumor sphere formation. 41

Glucose can induce the tyrosine phosphorylation of NEDD4, thereby activating the activity of NEDD4 E3 ligase. However, it needs to be made clear which upstream signaling pathway is involved in NEDD4 phosphorylation. While the upstream signaling pathway involved in NEDD4 phosphorylation is not entirely understood, previous studies have shown that growth factors such as fibroblast growth factor or epidermal growth factor can induce NEDD4 tyrosine phosphorylation through Src kinase. 42 Instead, it has been suggested that the tyrosine kinase. Yes, the closest member of the Src family kinase (SFK) to Src may be involved in glucose-induced NEDD4 phosphorylation. Previous studies have also shown that glucose activation of SFK is essential for glucose-induced NEDD4 activation. This suggests that SFKs may be involved in the upstream signaling pathway that leads to NEDD4 phosphorylation in response to glucose. 43

Hyperglycemia or hyperglycemic state can affect cancer development and progression. Studies have shown that hyperglycemic conditions can promote a more aggressive phenotype in various cancers, including breast and liver cancer. In diabetic patients, hyperglycemia is an important cause of increased cancer mortality. High glucose conditions increased the phosphorylation of histone H3 at serine 10, which is associated with increased cell proliferation. 44

The preferential expression of PKM2 protein promotes the increase of glycolysis

The preferential expression of Pyruvate kinase isozyme M2 (PKM2) is related to increased aerobic glycolysis and the growth advantage of cancer cells. 45 After the depletion of DNA methyltransferase three beta (DNMT3β) or Brother of the Regulator of Imprinted Sites (BORIS) and the mutation of Bardet–Biedl syndrome (BBS) at exon 10 of PKM, the splicing transition from PKM2 to PKM1 isomer is related to the reversal of the Warburg effect, which further inhibits the growth of breast cancer cells. Although the observed reversal of the Warburg effect may not be entirely due to the splicing transition caused by DNMT3β and BORIS, it can partially explain the cause of poor prognosis or poor growth of breast cancer associated with DNMT3β 46 and BORIS. 47

The effect of glucose on OGT and O-GlcNAcylation

High glucose levels in cells have been found to increase the concentration of UDP- N -acetylglucosamine (UDP-GlcNAc), which in turn increases the overall O-β-N-acetylglucosamine (O-GlcNAc) levels. 48 O-GlcNAcylation refers to an O-GlcNAc moiety that attaches to a serine or threonine residue on nuclear or cytoplasmic proteins. 49 The addition and removal of GlcNAc to proteins are catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. 50 O-GlcNAcylation regulates a variety of cellular processes, such as nutritional sensing, cell cycle progression, transcription, translation, epigenetic regulation, and protein-protein interactions. 50 , 51 , 52 , 53 Glycosyl groups of O-GlcNAc are considered to mediate glucose homeostasis and stress response, serving as a signaling cascade. 54

Elevated O-GlcNAcylation levels have been observed in different types of cancer; It is noteworthy that the inhibition of OGT has been demonstrated to impede tumor growth in various models. 55 , 56 , 57 Among many eukaryotic initiation factors in the translation mechanism, eukaryotic initiation factor 4E (eIF4E) is a key factor regulating the initiation of translation, which is also modified by O-GlcNAc in liver cancer. 53 O-GlcNAcylation has been shown to be involved in regulating protein stability. Specifically, at T168/T177, O-GlcNAcylation protects eIF4E from degradation, resulting in increased eIF4E protein levels. Given the fact that the high expression of eIF4E indicates a poor prognosis of HCC, the OGT-eIF4E axis plays a critical role in the progression and prognosis of HCC. Moreover, OGT activates the stem cell potential of HCC cells by upregulating eIF4E. These results indicate that glucose promotes the proliferation of hepatoma cells and stem cell-like potential through OGT. Currently, several pathways have been proposed that implicate O-GlcNAcylated proteins in the link between tumorigenesis and hyperglycemia. Specificity protein 1 (Sp1) is an important transcription factor in cells. In cancer, higher levels of Sp1 are associated with tumor cell survival, proliferation and invasion, and angiogenesis within the tumor. Sp1 is O-GlcNAcylated, and at least one O-GlcNAc site is associated with its stability. 58 Therefore, Hyperglycemia and high glucose increase O-GlcNAcylation of Sp1, thereby promoting tumor cell metabolism and survival. 59 Elevated glucose levels enhance the transcriptional activity of at least two members of the NF-kB family, p65 and c-Rel, via O-GlcNAcylation modification. The NF-kB pathway is known to be associated with the Hexosamine Biosynthetic Pathway, which has been shown to promote the growth of tumor cells. 60 Similar to its role in regulating NF-kB, high glucose conditions increase the activity of the β-catenin pathway, amplifying the response of different human cancer cells to Wnt through O-GlcNAcylation. 61 O-GlcNAc has been found to stimulate Yes-associated protein (YAP) function, which plays a crucial role in tumorigenesis. When GlcNAc and PUGNAc induce Hyper-O-GlcNAcylation or when OGT is overexpressed, the transcriptional activity of YAP/TEAD increases along with the expression of their target gene CTGF, which is related to cell proliferation 62 (Fig. 1 ).

The effect of glucose on OGT and O-GlcNAcylation. GlcNAc is an O-β-N-acetylglucosamine moiety attached to a nuclear protein, cytoplasmic protein serine, or threonine residue. The addition of GlcNAc to proteins is catalyzed by OGT, while its removal is catalyzed by OGA. Currently, several pathways have been proposed that implicate O-GlcNAcylated proteins in the link between tumorigenesis and hyperglycemia. O-GlcNAcylation stabilizes SP1, β-catenin and YAP proteins promoting expression of target genes and transcriptional activity of NF-kB pathway. O-GlcNAc O-β- N -acetylglucosamine, OGT O-GlcNAc transferase, OGA O-GlcNAcase, SP1 Specificity protein 1, YAP Yes-associated protein

Glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub)

Glucose starvation inhibits H2Aub, a histone modification related to gene suppression. 63 , 64 , 65 The inhibition of H2Aub levels by glucose deficiency is independent of energy stress-mediated AMP-activated protein kinase(AMPK) activation and may result from nicotinamide adenine dinucleotide phosphate (NADPH) depletion and subsequent inhibition of BMI1, a component of polycomb repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin sections. 66 , 67 , 68 , 69 , 70 , 71 Comprehensive transcriptomic and epigenomic analysis link glucose starvation-mediated H2Aub suppression with the activation of genes related to the endoplasmic reticulum (ER) stress response. 72 The epigenetic mechanism plays a role in glucose starvation-induced cell death, and the pharmacological inhibition of glucose transporter 1 (GLUT1) and PRC1 synergistically promotes ER stress and inhibits tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism that couples the availability of glucose with the ER stress response. 73

The role of ncRNA in the glucose metabolism

Non-coding RNA (ncRNA) is a class of functional RNA molecules that regulate the expression of target genes without being translated into proteins. Based on their size, ncRNAs can be classified into small ncRNAs (including microRNA, small interfering RNA, PIWI-interacting RNA, small nucleolar RNA, and small nuclear RNA) and long ncRNAs(lncRNA). The transcription and processing method of lncRNA is similar to that of microRNA. Functionally, lncRNA exerts various mechanisms of action in cells, including direct transcriptional regulation, histone modification, and regulation of the transcription of regulatory factors acting as bait-binding sites. Gene expression profiles indicate that lncRNA is expressed in a tissue-specific or cell-specific manner and has different expressions under different pathophysiological conditions. ncRNA is associated with a variety of cancers. mircoRNA and lncRNA, known as oncogenes and tumor suppressors, act on receptor tyrosine kinase (RTK) and hypoxia-mediated pathways. Anticancer microRNA replacement therapy has a high potential in cancer treatment. For example, the drugs for bone metastasis and colon cancer, which are microRNA mimics, resulted in a significant decrease in tumor size. 74

ncRNAs modulate glucose transport in cancer cells by elevating GLUT levels. Among the 14 GLUT isotypes, 75 , 76 GLUT1 is known to be overexpressed in cancer. ncRNA is involved in the regulation of GLUT1 expression. The lncRNA neighbor BRCA1 gene 2 (NBR2) promotes cell survival by upregulating GLUT1 expression. 77

In addition to regulating GLUTs, ncRNAs also modulate key glycolytic enzymes involved in the three critical steps of glycolysis. The first is the phosphorylation of glucose by hexokinases (HKs) to produce glucose 6-phosphate (G6P). In addition to the ubiquitously expressed HK1, cancer cells overexpress HK2, which is critical to the Warburg effect because phosphorylated glucose is trapped in the cytoplasm. Other regulators of HK2 are microRNA-143 and -145, which cluster on chromosome 5q32 and are down-regulated in many cancer types. 78 , 79 The second key step of glycolysis is the conversion of fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P) under the catalysis of phosphofructokinase 1 (PFK1). TAT-activated regulatory DNA binding protein (TARDBP), which is highly expressed in hepatocellular carcinoma (HCC), regulates glycolysis by inducing the expression of the platelet isoform PFK1 (PFKP). TARDBP inhibits the expression of microRNA-520a/b/e by directly binding to its promoter region, preventing it from binding to the 3’-UTR of PFKP and thereby inhibiting protein expression. The last key step of glycolysis is catalyzed by pyruvate kinase (PK). Cancer cells use various functional gain strategies to increase glycolysis. Although PK function can be attenuated by expressing the low-affinity dimer form of PKM2, the tetrameric form of PKM2 and PKM1 play a role in the physiological phosphoenolpyruvate level of normal cells. Some have found that microRNA expression PKM2 adjustment disorders in cancer. microRNA-133a/b is downregulated in several types of cancer. 80 , 81 microRNA-326 displayed direct targets and inhibited the expression of PKM2. In addition, microRNA-326 levels and high levels of glioma cells PKM2 are negatively correlated, indicating endogenous PKM2 adjustment mechanism. 82

Many ncRNAs have been found to regulate PI3K/Akt/mTOR signaling. We are here to focus on ncRNAs known to be associated with the Warburg effect. microRNA-451 can down-regulate the expression of GLUT1 in glioma cell lines by inhibiting the PI3K/Akt pathway and glycolysis. 83 LncRNA Maternally Expressed Gene (MEG) 3 is expressed in various normal tissues and is silenced in several primary human tumors and cell lines. Ectopic expression of MEG3 leads to the accumulation of p53 and altered expression of p53 target genes in tumor cells, leading to growth inhibition. These findings indicate that MEG3 can negatively regulate glycolysis through p53 and act as a tumor suppressor. 84 , 85

The target therapy concentrated on glucose metabolite

So far, there are several target points that may be correlated with the therapy. The primary approach is targeting GLUTs. It included several preclinical glycolytic inhibitors such as phloretin, fasentin, STF-31, WZB117, ritonavir, and silybin. 86 The silybin has entered Phase I clinical trial. 87 Another approach is to target HK enzymes, with 2-deoxy-D-glucose (2-DG), 88 , 89 and lonidamine (LN) 90 currently under Phase II clinical trial, and resveratrol, genistein-27, benserazide, astragalin, and chrysin under preclinical research. 91 , 92 , 93 , 94 , 95 However, targeting HK2 in anticancer therapy is challenging due to the toxicity of normal cells and the high doses required by current inhibitors. Additionally, targeting specific HK subtypes is difficult due to the highly conserved domains of HK1 and HK2. Targeting PI3K/Akt/mTOR pathway is another option, with many inhibitor agents under testing in preclinical and early clinical studies as targeted anticancer therapies. These agents include Afuresertib, Uprosertib, and Ipatasertib. 96 However, the single therapy is only efficacy in malignancy with PIK3 mutation or PTEN deficiency. 97 In addition, mTOR inhibitors have shown clinical benefits in several tumors, such as neuroendocrine, endometrial, and breast cancers. 98 , 99 Rapalogs, a mTORC1 inhibitor, shows limited activity in clinical trials as single anticancer agents, probably due to the various cross-talks of the complicated mTOR pathway with other signaling pathways. 100 The newer generations of dual mTOR kinase inhibitors (PP242, NVP-BEZ235) are less liable to induce tumor resistance than the rapalogs. These agents are tested in preclinical studies and recently entered some clinical trials. 101 , 102 However, the great metabolic heterogeneity and cellular plasticity observed in solid tumors make metabolic inhibitors unlikely to become effective as monotherapy for cancer. Therefore, combination therapy is the future area of focus.

Metabolite sensing and epigenetic regulation of fatty acid metabolism

With the concept of tumor metabolism micro-environment, fatty acid metabolism in cancers have been increasingly focused on. The oxidation of fatty acids provides energy in the form of ATP and NADH, while its synthesis provides the foundation for cell structure. 103 To meet the specific growth needs of tumor cells, there are increased fatty acid uptake and synthesis, as well as decreased fatty acid oxidation in cancer cells. 1 , 2 Regulating abnormal fatty acid metabolism inhibits tumorigenesis and improves cancer-free survival. 104 , 105 Currently, there are many anti-cancer drugs targeting fatty acid metabolism, such as FASN inhibitors, ASSC2 inhibitors and so on. 106 Meanwhile, due to the changes in fatty acid metabolism in cancers, certain specific fatty acids may serve as potential biomarkers for cancer diagnosis. 107 , 108

Cells convert abnormal fatty acids concentration and categories into a series of biochemical information through metabolite sensor-mediated signal transduction and metabolite conjugate sensing mechanism. 7 , 104 Also, fatty acids and their intermediate metabolites play important roles in the origination and development of cancer by regulating epigenetic mechanisms. With the deepening of research, some new small molecule tools are constantly improving, which provides the possibility for in vivo lipidomics. 109

Signal transduction of fatty acid and its derivatives

Gpcr is a recognizer of fatty acid and its derivatives.

Sensors of fatty acids and their intermediate metabolites are mainly various types of GPCRs, such as GPR41, GPR43, GPR109A, GPR78, GPR84, GPR120, etc. Among them, GPR41, GRR43, and GPR109A recognize SCFAs. GPR43 prefer short-chain fatty acids, acetate, and propionic acid. 110 GPR41 mainly binds to amyl acetate, butyrate, and propionate. GPR109A and GPR109B show 96% identity at the protein level. In short-chain fatty acids (SCFAs), only butyrate activates GPR109A, 111 , 112 while any short-chain fatty acids can activate GPR109B. 111 GPR84 recognizes medium-chain fatty acids(C9-C14). 113 GPR120 recognizes ω-3 fatty acids and long-chain fatty acids. 114 , 115 GPR131 can identify primary and secondary (bacterial origin) bile acid metabolites. 116

After the metabolites are recognized by their specific sensors, they mainly transmit information through two pathways. The first one is through G protein pathway. Specifically, GPCRs can regulate effectors such as enzymes and ion channels mentioned in the parts of glucose. 31 , 32 , 33 For example, by activating MAPK, PI3K, mTOR, etc., the changes in cell metabolism can promote the progression of cancers. 117 , 118 , 119 , 120 , 121 , 122 The MAPK, PI3K, and mTOR signal pathways play important roles in maintaining cell proliferation, growth, and survival, 123 , 124 and are often abnormally altered in various cancers (Fig. 2 ). Notably, mTORC1 complex regulates lipid synthesis through multiple mechanisms by regulating the binding protein of sterol regulatory element-binding proteins (SREBP). 125 SREBP transcription factors are the main regulators controlling the expression of most fatty acid synthesis enzymes. It phosphorylates Lipin1, preventing it from translocating to the nucleus, thereby inhibiting SREBP1/2-dependent transcription. 126 Also, it can increase the activity and expression of peroxisome proliferator-activated receptor γ (PPARγ) which is a transcription regulator of abiogenic genes. 127 , 128 Through these mechanisms, mTORC1 increases the transcription of adipogenic genes, including key enzymes in fatty acid syntheses, such as acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY), and fatty acid synthase (FASN), which are related to the progress of cancers, at the same time, a variety of inhibitors targeting key enzymes of fatty acid synthesis pathway have been developed. 106 Specifically, GPR41, GPR43, and GPR109A are coupled with Gi/o. After binding with the ligand, they reduce the activity of adenylate cyclase and inhibit cyclic adenosine monophosphate (cAMP) through a pertussis toxin (PTX) sensitive mechanism. Besides, GPR43 also has Gq/11-dependent activity which can contribute to the activation of phospholipase C (PLC)-β and the formation of inositol 1,4,5-triphosphate (IP3). Then, IP3 binds and opens the endoplasmic IP3 gated calcium channel, causing the release of calcium into the cytoplasm. 129 , 130 , 131 , 132 , 133

GPCRs-mediated short-chain fatty acid signal transduction. Dietary fiber in the diet can produce short-chain fatty acids under the action of intestinal microorganisms. Short-chain fatty acids can activate the corresponding GPCRs to cause a series of downstream signaling and trigger a variety of biological functions. GPCRs activation can induce changes in cell shape and movement, induce Ca 2+ or K + efflux, or trigger downstream PI3K/MTOR/MAPK pathways. PI3K can phosphorylate PIP2 to PIP3 which can activate AKT, promoting cell proliferation and angiogenesis by phosphorylating different factors, regulate cell cycle, inhibiting apoptosis and regulating NF-κß and p53 signaling pathway. mTORC1 phosphorylates Lipin1, inhibits SREBP1/2-dependent transcription, and increases PPARγ activity, thereby increasing the transcription of ACC, ACLY, and FASN. The MAPK pathway maintains the expansion of key molecules in the process of cell proliferation, growth and survival, and promotes EMT of cancer cells. RAS is not only an activator of MAPK pathway, but also an activator of P13k/AKT/mTOR pathway. In addition, GPCR can also send signals through β-arrestin, which can inhibit the activation of NF-κB and the production of pro-inflammatory cytokines. PI3K phosphatidylinositol 3 kinase, MTOR mitogen-activated protein, PPARγ peroxisome proliferator-activated receptor γ, ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, FASN fatty acid synthase, EMT epithelial mesenchymal transformation, SREBP sterol regulatory element binding protein

The second pathway is mediated by β-arrestin-2. GPR109A and GPR43 are involved in the binding of β-arrestin, some of which are related to the inhibition of nuclear factor-kappa-gene binding (NF-κB), β-arrestin-2 directly interacts with NF-κB inhibitor (IκBα), preventing the phosphorylation and degradation of IκBα. 134 However, this pathway is mainly related to anti-inflammatory and desensitizing effects, 118 , 120 and its role in cancers is still unclear. Noteworthy, SCFAs and their intermediate metabolites bind to different subunits of G protein or β-arrestins, leading to different results in different cells. For example, GPR109A signaling reduces cAMP levels in adipocytes, while leading to the production of prostaglandin D2 (PGD2) in Langerhans cells and macrophages. 135

Abnormal status of fatty acids signal transduction in cancers

GPR109A is a G protein-coupled receptor found on the surface of intestinal epithelium cells and immune cells. Studies have shown that the expression of GPR109A mRNA is suppressed in primary colon cancer tissues and colon cancer cell lines. Also, the expression of GPR109A is significantly higher in acute promyelocytic leukemia cells and lung cancer cells. 136 Niacin and butyric acid as GPR109A agonists contribute to the ectopic expression of GPR109A in colon cancer cells, inducing cell apoptosis. 112 Colonic epithelial cells use butyrate produced by gut microbiota to synthesize β-hydroxybutyrate. 3-Hydroxy-3-methylglytaryl-CoA synthetase 2 (HMGCS2) controls the synthesis of ketone body β-hydroxybutyrate, but its activity is inhibited in cancers, resulting in the lower level of β-hydroxybutyrate produced by cancer cells. As an endogenous agonist of GPR109A, β-hydroxybutyrate acts through GPR109A which acts as a tumor suppressor. Specifically, when the synthesis of β-hydroxybutyrate is reduced, the tumor suppressive function of GPR109A is weakened, promoting the progression of cancers. 137 In the colon cancer model related to inflammation, the number of colon polyps of GPR109A−/− mice is significantly more than wild-type mice under the induction of the same carcinogenic factors. 115 The deficiency of GPR109A also increases the incidence of colon cancer. 115 Niacin can inhibit colitis and AOM + DSS induced carcinogenesis, and this effect has been shown to depend on GPR109A. 115 Overall, lower butyrate and β-hydroxybutyrate synthesis in cancers inhibits GPR109A signal transduction and promotes carcinogenesis.

Besides, consumption of dietary fiber is associated with a reduced risk of carcinogenesis in breast cancer, prostate and other cancers, as dietary fiber can be degraded by the gut microbiota into short-chain fatty acids (SCFAs). Breast epithelial cells express GPR109A, whereas primary human breast tumor tissues do not express it. Enhanced expression of GPR109A can induce apoptosis and cell cycle arrest in breast carcinoma cell lines. In addition, GPR109A deficiency leads to early development and metastasis of breast cancer. 138 Moreover, the knockdown of GPR109A leads to increased proliferation of breast cancer cells and GPR109A activation inhibits tumor growth. 115 , 138 , 139 This phenomenon can be explained by the lack of dietary fiber/SCFAs which leads to the development, differentiation or accumulation of inflammatory immune cells in the intestine and local lymph nodes. These inflammatory cells spread or secrete inflammatory factors, inducing inflammation and enhancing carcinogenesis. Therefore, it is essential to investigate whether dietary fiber or SCFAs inhibit carcinogenesis in organs away from the intestine by inhibiting intestinal pathogenic bacteria and/or inflammatory cells. 140 At the same time, it indicates a possibility: the lack of dietary fiber/SCFAs inhibits the tumor suppressor signal of GPR109A, which is beneficial to the development of cancer. Based on the above, GPR109A agonists can be used for cancer prevention, 137 such as β-hydroxybutyrate and dietary fiber. Meanwhile, synthetic GPR109A-specific agonists MK1903, 141 acifran, 142 5-aminonicotinic acid (5-ANA), 143 GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) 144 has been explored for its role in vascular and inflammatory diseases, but no preclinical and clinical studies have demonstrated their effectiveness in tumors. To find a strong targeting GPR109A agonist will provide a huge potential in tumor therapy. But there are still many problems that need to be solved before the clinical application of anti-cancer drugs against this target.

HCA1(GPR81)/HCA3(GPR109B)

Hydroxycarboxylic acid receptor (HCA) receptor family includes three members, primarily expressed on adipocytes, whose activation can inhibit lipolysis in these cells. The activator of HCA1 is lactic acid, a glycolysis product; the endogenous agonist of HCA2 is the ketone body-3-hydroxybutyrate (3HB); the endogenous agonist of HCA3 is the intermediate of fatty acid β-oxidation (FAO)—3-hydroxyoctanoate (3HO). 145 , 146

The expression of HCA1 and HCA3 mRNA in tissues of human breast cancer patients is significantly increased compared with normal tissue samples and primary breast cancer cells, which means enhanced inhibition of lipolysis of adipocytes. In addition, HCA1 mRNA expression is significantly increased in lung cancer cells and acute lymphoblastic leukemia cells. The metabolism of cancer cells is disrupted by the knockdown of HCA3 and HCA1, resulting in reduced viability reduction and/or cell death. Etomuslim and peroxicillin, the fatty acid β-oxidation inhibitors, can prevent HCA3 knockdown-induced cell death in breast cancer cells. 136 Similarly, the presence of HCA2 and HCA3 mRNA transcripts has also been demonstrated in LoVo colorectal adenocarcinoma cells, 139 and HCA1 has been confirmed in several cancer cell types including colon cancer, lung cancer and breast cancer. 147

HCA1 acts as a lactate receptor, but it can also affect fatty acid metabolism. In mice, HCA1 mediates anti-lipolysis in an insulin-dependent manner. 148 Due to the high rate of glycolysis in cancer cells, high levels of lactic acid are produced and exported. In this way, a sufficiently high concentration of lactic acid activates HCA1, which subsequently leads to the inhibition of lipolysis and FAO. 147 The knockdown of HCA1 expression will be accompanied by increased mRNAs of HCA2 and HCA3, serving as secondary metabolic monitoring to detect changes in cellular metabolism. 136 Lactate acts as a signaling molecule by acting as an agonist for GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, lactate produced by cancer cells activates GPR81 on cancer cells; in the paracrine pathway, lactate produced by cancer cells activates GPR81 on immune cells, endothelial cells, and adipocytes present in the tumor stroma. The ultimate result of GPR81 activation is to promote angiogenesis, immune evasion and chemoresistance. 149 Lactate dehydrogenase A(LDHA) is the main subtype responsible for lactate production which is upregulated in cancer. LDHA inhibitors have been shown to possess anticancer effects in vitro and in vivo. 150 , 151 , 152 , 153 However, LDHA is necessary for normal biological function, so blockading LDHA as a cancer therapy may have many off-target effects and no clinical studies have been carried out. Silencing GPR81 significantly reduced the expression of lactate transporters monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4) and their chaperones protein CD147 in pancreatic cancer cell lines. 154 CD147 has also been proven as a potential drug target to disrupt MCT membrane insertion and function for cancer therapy but also has limitations due to its necessity for normal activities. 155

Knockdown of HCA3 induces a significant cell death and cell viability reduction in three breast cancer cells: BT-474, HCC1954 and HCC38. 136 Here is one possible explanation: cancer cells shunt glucose to anabolic processes instead of oxidizing glucose to produce ATP, then energy needs must be met in other ways, such as FAO. 2 By increasing lipolysis and subsequent FAO, acetyl-CoA which can enter the citric acid cycle is produced. 2 When the level of acetyl-CoA exceeds the need of the citric acid cycle, ketone bodies (such as 3HB) are generated. Within the presence of glucose, by eliminating this negative feedback mechanism, cancer cells can maintain a high proliferation rate as well as produce ketone bodies, which can be used again as an energy source. 156 According to Ahmed and others, HCA3 is a sensor of a raised level of 3HO, which is an indicator of a high β-oxidation rate. Activation of HCA3 inhibits the release of free fatty acids, thereby reducing its availability for FAO. In this way, it constitutes another negative feedback mechanism to control lipolytic activity. 146 , 157 HCA3 plays a central role in controlling the balance of lipid/fatty acid metabolism in breast cancer cells. Knockdown of HCA3 leads to an uncontrollable increase of FAO in cells, which is the cause of breast cancer cells death. There are few studies on GPR109B antagonists which is worthy of further exploration.

The expression of GPR43 is lost in human colon cancer cell lines and sharply down-regulated in colorectal adenocarcinoma. 158 GPR43 deficiency promotes the development of both colon adenoma in ApcMin + DSS (dextran sulfate sodium) mice and the adenomas to adenocarcinoma in azoxymethane/ dextran sulfate sodium (AOM/DSS) mice. 159 GPR43 deficiency or lacking of fiber in diet can lead to increased recruitment and migration of neutrophils, 160 which cause inflammation. There are two explanations for the specific mechanism: First, SCFAs may affect the neutrophil L-selectin shedding through GPR43. 161 However, there are also experimental results that showed SCFA treatment can increase L-selectin expression and L-selectin mRNA levels on the surface of neutrophils, 162 which may be related to the cancer-promoting effect caused by GPR43 deficiency. It also indicates that acetate salt has potential therapeutic effects for diseases that need to control the neutrophil influx. The second one is that the loss of GPR43 leads to the destruction of the intestinal barrier integrity which promotes the failure of CD8 + T cells and the excessive activation of dendritic cells(DCs), leading to the death of mice and promoting the occurrence of colon cancer in mice. 163 GPR43 deletion promotes the carcinogenesis of colon cancers in mice by reducing the integrity of the intestinal barrier, increasing the bacterial burden of cancers, and changing the phenotype and function of dendritic cells and CD8 + T lymphocytes. 163 Second, GPR43 can differently activate protein kinase B (AKT) or extracellular regulated protein kinases (ERK) signals, and increase the regulation of IL-22 produced by innate lymphoid cell 3 (ILC3). Acetate can enhance the expression of IL-1 receptor (IL-1R) through GPR43, promoting ILC3 to produce IL-22 after stimulation with IL-1β. 164 Also, GPR43 can promote the expansion of ILC3 which is essential for intestinal homeostasis and host defense. 165 But its exact role in cancers remains to be further investigated. 166 In summary, SCFAs can participate in anti-cancer tumor immunity through GPR43, and combine the metabolic microenvironment with the immune microenvironment, which will be a field that worth exploring. Several GPR43 agonists have been reported, such as 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB) and AZ1729, but only in preclinical studies in the field of inflammation, its role in cancers is still unknown. 167 , 168 , 169 , 170

GPR84 is the recognizer of medium-chain fatty acids (C9–C14) including capric acid (C10), undecanoic acid (C11), and lauric acid (C12). 113 The levels of GPR84 expression are significantly upregulated in human and mouse acute myeloid leukemia (AML) leukemic stem cells (LSCs) compared to normal hematopoietic stem cells (HSCs). GPR84 depletion impairs LSCs’ function and inhibits the development of aggressive and drug-resistant subtypes of AML. At the same time, the expression level of GPR84 was significantly related to the survival time of AML patients. 171 , 172 Mechanistically, GPR84 overexpression induces activation of the β-catenin transcriptional cofactors Tcf7l2 and c-Fos as well as genomes associated with Wnt signaling. 173 GPR84 antagonists have been evaluated in clinical trials to treat ulcerative colitis, idiopathic pulmonary fibrosis, and nonalcoholic steatohepatitis. 174 GLPG1205 as an antagonist of GPR84 has accomplished clinical a phase II trial which is the potential to treat cancers 175 as well as Compound 33 with improved potency of GPR84 is possible to become a candidate drug for cancer therapy which needs further clinical research. 174 On the other hand, CRC cells downregulate the expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs), thereby promoting osteoclastogenesis in an IL-11-dependent manner. Therefore, GPR84 may be a potential therapeutic target to alleviate bone destruction caused by CRC metastasis. Additionally, GPR84 is involved in immune regulation as its expression has been described predominantly in immune cells. 176 A study proved that GPR84 enhanced macrophage phagocytosis of adipocyte plasma membrane-associated protein (APMAP)-deficient cancer cells. 177 This means that CPR84 may be a key point linking the tumor metabolic microenvironment with anti-tumor immunity. LY-237 and 6-octylaminouracil have been reported to act as an agonist at GPR84 which is currently in preclinical research. 178 , 179 Given the dual role of GPR84 in cancer, it would be meaningful to explore its specific mechanisms in different types of cancer.

GPR40 is overexpressed in breast tumors as a long-chain fatty acid receptor. One of its ligands, oleic acid (OA) has been shown to participate in cancer cell proliferation. 180 Exogenous supplement of oleic acid enhanced the fluidity of the plasma membrane and promoted the invasion and migration of HCC cells. 181 GPR40 overexpression contributed to the oleate-induced proliferation of cancer cells. Using RNA interference, when the GPR40 gene was silenced, oleate-induced proliferation of cancer cells decreased. 182 In addition, compared with normal ovaries, GPR40 expression is significantly increased in high-grade carcinoma and is higher in in advanced stage disease. It was also found that GPR40 was overexpressed in prostate cancer (PCa) tissue compared with benign prostatic hyperplasia tissue, and OA promoted the aggressive phenotype of PCa cells through FFA1/GPR40, calcium and PI3K/Akt signaling. 183 These findings suggest that GPR40 plays a cancer-promoting role. The GPR40 antagonist, GW100 resulted in growth inhibition in EOC cell line which means GPR40 is a potential target for cancer therapy. 184 In addition, there is another small molecule antagonist DC260126 that targeted GPR40, but its application in cancer has not been reported yet. 185

GPR120 (encoded by FFAR4 gene) is a receptor for long-chain fatty acids, activated by ω-3 polyunsaturated fatty acids (PUFAs), and expressed in many cell types. 186 GPR120 was overexpressed in breast cancer cells and was important for the acquisition of chemoresistance. GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism in breast cancer cells. GPR120 antagonist AH7614 or GPR120-siRNA significantly compromised chemoresistance. 187 , 188 Also, GPR120 was found to promote tumor cell migration and invasion in pancreatic cancer, colorectal carcinoma(CRC) and bone cancer. 189 , 190 However, it has also been shown that GPR120 on M2 macrophages may be beneficial for DHA-mediated anti-prostate cancer effects. 191 At the same time, the loss of GPR120 in the intestinal epithelial cell leads to increased intestinal permeability, microbiota translocation, and dysbiosis, implying that GPR120 receptors are critical for maintaining mucosal barrier integrity and preventing CRC development. 186 And other studies have found that it acted as a tumor suppressor because it can suppress tumor cell migration and invasion in melanoma and lung cancer. 189 Recent studies have developed potent and selective GPR120 agonists such as GW9508, 190 TUG-891 192 and compound 39 (a benzofuran propanoic acid analog), 193 which are expected to become a new kind of anti-cancer drug. A new study has found that GPR120 recognizes single and double bonds in fatty acids and induces different downstream signaling pathway transduction mechanisms, which provides a theoretical basis and structural basis for the development of new high-efficiency unsaturated fatty acid drugs that precisely target GPR120, 194 and this founding may explain the dual role of GPR120 in cancers.

In breast cancer, inhibition of GRP78 decreases mitochondrial transport of fatty acids. Thus, fatty acid oxidation is attenuated, leading to the accumulation of essential polyunsaturated fatty acids in the intracellular space. Changes in intracellular fatty acids further increased the serum level of monocyte chemotactic protein 1 (MCP-1) and reduced the expression of the self-recognizing identifier CD47 in the tumor. In addition, inhibition of GPR78 can enhance macrophage infiltration, suggesting a potential link between fatty acid metabolism and cancer immunity, 195 which means GPR78 may serve as a potential drug target against metastatic human lung cancer. Currently, an antibody against the COOH-terminal domain of GPR78 (anti-CTD antibody) can downregulate pro-proliferative signaling and upregulate p53 in prostate cancer cells and melanoma cells, 196 and GPR78 protein expression was significantly regulated by miR-936 in laryngeal squamous cell carcinoma (LSCC) cells, 197 suggesting two possible approaches to target GPR78, but no relevant clinical trials have yet been conducted.

Signal transduction of fatty acid derivatives

ATP produced by fatty acid oxidation plays an important role in cell bioenergetics, Src kinase auto-phosphorylation and signal transduction. 198 ROS produced by fatty acids oxidation of mitochondria contributes to TGF-β, which induces EMT and invasiveness of A549 cancer cells. 199 But specific metabolite sensing mechanism of ATP and ROS needs further study.

Other lipids derived from fatty acids also have signaling effects that affect metastasis. Sometimes it is through indirect cancer cell autonomic mechanisms. For example, sphingosine-1-phosphate (S1P) is exported from endothelial cells to the circulatory system via the transport protein SPNS2. Knockout of SPNS2 can disrupt the movement of white blood cells from lymphoid tissues into the blood, which paradoxically leads to an increase in the ratio of anti-tumor effect T cells to immunosuppressive T cells, and enhances the inhibitory effect on metastasis. 200 Fatty acid metabolism and its signal transduction pathways may produce attractive targets for inhibiting metastasis, which is also one of the directions for developing targeted drugs. Prednisone’s bacterial side chain cleavage product 1,4-androstadiene-3,11,17-trione can interact with androgen receptors to contribute to the expression and function of downstream targets, showing pro-proliferation function in prostate cancer cells, but the specific proliferative mechanism needs further study. 201 Urolithin A destroys the expression and function of Rac family small GTPase 1 (Rac1) and protein activated kinase 1 (Pak1). Subsequently, it also destroys actin depolymerization and migration. 202 The ability of cancer cells to migrate and invade requires a recombinant actin cytoskeleton, 203 while Rac1 is the main regulator of the actin cytoskeleton. 204 Many other studies have also shown that Rac1 is overexpressed in many cancers, and the loss of Rac1 activity inhibits tumor growth. 205 , 206 In addition, Uro-A can lead to a dose-dependent anti-cloning effect by increasing the aging-related β-galactosidase activity. 207 Therefore, the application of urolithin A in cancer prevention or adjuvant therapy is promising.

Overall, GPCRs are essential in fatty acid-related metabolite sensing mechanisms as the main receptor of fatty acids. The concentrations of metabolites are converted into a series of chemical signals which affect the carcinogenesis and metastasis of cancer through binding with their specific receptors. Interestingly, metabolite receptors’ expression levels in cancers are also different from normal cells, which can affect the phenotype of cancers. These mechanisms explain well how changes in fatty acid concentration affect cancer processes. At the same time, these signal transduction pathways and the differential expression levels of metabolite receptors also provide a direction for the development of cancer-specific targeted drugs.

The function of fatty acid and its metabolites in epigenetics regulation

Fatty acids indirectly affect enzymes related to epigenetics, short-chain fatty acid.

Short-chain fatty acids (SCFAs) mainly include acetic acid, propionic acid, butyric acid, valeric acid, isobutyric acid, isovaleric acid, caproic acid, etc. 208 It can be produced by intestinal microbiota and its types and quantity mainly depend on the composition of intestinal microbiota and the consumption of dietary fiber. 209 SCFAs is a natural inhibitors of histone deacetylase (HDAC) which allows gene transcription, butyrate is the most effective ligand while acetate is the least effective one. 114 , 119 , 210 , 211 , 212 SCFAs regulate epigenetics mainly by changing the function of HDAC. HDAC inhibition causes histone acetylation to produce negatively charged histones. When they interact with negatively charged DNA, the chromatin structure is loosed, producing a transcriptionally active conformation that upregulates tumor suppressor genes of CRC in epigenetics. 213 And butyrate can induce a four-fold increase in the transcription level of TNF receptor superfamily member 25 (Tnfrsf25) and death associated protein kinase 1 (Dapk1) (apoptosis-related genes), the increased expression of these genes may be due to the reverse effect of butyrate on histone deacetylation 214 as the promoter regions of Dapk1 and Tnfrsf25 are close to the site where histone modification occurs. 215 Meanwhile, HDAC inhibition can also inhibit or trigger the expression of miRNA in some cancer samples. 216 For example, HDAC inhibition can trigger the expression of miR-15a and miR-16 in CLL, which expression is usually reduced in cancer. 217 Acetylation can also promote the activation, nuclear translocation and DNA binding of transcription factors (such as STAT3, NF-kB, FoxP3, N-FAT and RUNX1). 118 , 218 , 219 In addition, sodium propionate (SP) affects the expression of survivin and p21, inducing cell cycle arrest especially in the G2/M phase, and then leading to apoptosis that can be applied to the targeted treatment of lung cancer. 220 Additionally, SP can upregulate the surface expression of MHC class I related chain A/B(MICA/B) which is NKG2-D type II integral membrane protein (NKG2D) ligand by increasing overall acetylation and propionylation and then inhibiting lysine acetyltransferase (KAT), which is not independent on GPR41/GPR43 receptors, but functional mitochondria. 221 There are already some HDAC inhibitors, such as SAHA (Vorinostat), 222 , 223 , 224 entinostat, 225 valproate 226 and romidepsin. 227 Romidepsin and Vorinostat have been approved for the treatment of T-cell lymphoma by the FDA, 228 , 229 but current research has not shown that they can be used as colorectal cancer treatment drugs. There are currently several phase I clinical trials exploring the combination regimen of HDAC inhibitors to achieve better cancer treatment 230 , 231 and many novel HDAC inhibitors are undergoing phase I and II clinical trials. 232 , 233 In addition, SCFAs may directly affect the transcription of HDAC genes. 118 In GPR43-deficient mice, cycle adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) pathway is enhanced, resulting in the overexpression of HDAC. Similarly, more neutrophils infiltrated into tumors and the colon lamina propria in GPR43-deficient mice. In addition, butyric acid inhibits HDAC expression and methylation of inflammation inhibitory factors through GPR43. From this point of view, SCFAs are a kind of epigenetic inhibitor, which play a pivotal role in multiple stages of colon cancer. 159

Medium-chain fatty acids

In addition to SCFAs, it is worth noting that the latest research shows that the addition of medium-chain fatty acids C8 or C10 to glioblastoma cells can affect the citric acid cycle, affecting the Warburg effect, glutamine/glutamate metabolism and ketone body metabolism. C8 leads to an increased ketone body production while C10 mainly affects the cytoplasmic pathway by stimulating fatty acid synthesis. 234 , 235 Also, medium-chain fatty acids, like Valproic acid or valproate (VPA) inhibit HDAC, thus exerting similar anti-cancer effects to SCFAs in regulating epigenetics. 236

Acetone body

Acetone body can be used as both an energy substrate and signaling molecule. Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is one of the main regulators of ketogenic effects, which can integrate nutritional signals into the transcriptional network that regulates the activation of fatty acid β oxidation and ketogenic effects. β-hydroxybutyrate (3-OHB), a kind of ketone body, has been identified as a class I HDAC inhibitor, which establishes a link between liver lipid metabolites and epigenetics. 3-OHB binds to specific hydroxyl-carboxylic acid receptors, and then inhibits HDACs, FFARs, and the NOD-like receptor protein 3 inflammasome, resulting in the inhibition of lipolysis, inflammation, oxidative stress, cancer growth and angiogenesis. 237 Clinical research finds that the ketogenic diet with chemotherapy can improve the survival rate of patients with advanced local or metastatic breast cancer. 238 This evidence suggests that there is a close link between ketone bodies and tumor epigenetic regulation, and targeting ketone bodies may provide new ideas for cancer treatments. In addition to interfering with ketone body metabolism through diet, enzymes in the ketone body metabolic pathway may also be targets, such as 3-oxoacid CoA-transferase 1 (OXCT1) which can catalyze the first step and limit the rate of ketone body metabolism step. Studies have shown that the expression of OXCT1 is significantly increased in different types of cancer cells and provided great potential in cancer therapy. 239

ω-3polyunsaturated fatty acid (ω-3PUFA)

The epigenetic regulation of ω-3PUFA may be directly attributed to their electrophilic oxidized derivatives, which are produced through endogenous enzymatic or non-enzymatic pathways. 240 , 241 , 242 , 243 , 244 , 245 Electrophilic lipids act as epigenetic modifiers by directly adding to histones, regulating catalytic histone modification or DNA methylation of enzymes, and controlling miRNA expression. 246 , 247 , 248 , 249 , 250 ω-3PUFA can modulate epigenetic events to regulate cellular processes associated with carcinogeneses, such as proliferation, differentiation, inflammation, and angiogenesis, 251 which is expected to be an attractive dietary supplement to improve the prognosis of cancer patients. 252 The treatment of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can downregulate the expression of EZH2, which is the core component of polycomb repressive complex (PRC2), and PRC2 can lead to H3K27me3 modification 253 in vitro. On the other hand, EZH2 is closely associated with miRNA silencing. It can bind to the miRNA promoter and regulate the expression of miRNA and finally regulating epigenetics. 216 Fish oil rich in EPA and DHA can reduce breast cancer metastasis in mouse breast cancer models and reduce both the migration and the invasion of cancer cells by down-regulating the expression of CD44 in vitro. CD44 is a kind of cell surface protein that can combine matrix collagen and MMP-9 promoting extracellular matrix(ECM) remodeling. 254 Preclinical and clinical trials evaluating the pharmacokinetics, efficacy, and drug-related toxicity of CD44 monoclonal antibodies have been conducted in tumors with CD44 expression. 255 DHA also directly blocks the MMP-9 expression by inhibiting the PPARγ/NF-κB pathway. 256 In addition, DHA can induce Sirtuin 1 (SIRT-1) expression in a variety of cells including colonic epithelial cells, 257 , 258 an NAD + dependent histone deacetylase, which mainly targets histones and non-histone proteins including transcription factors. The combination of fish oil (FO) and pectin (butyrate) can enhance the apoptosis of colon cells, which is related to the expression of genes involved in apoptosis. 259 , 260 , 261 A study has found that dietary supplementation of pectin significantly increased the abundance of butyric acid bacteria in the gut, promoting butyric acid production, and enhanced the therapeutic effect of anti-PD-1 mAb, which establish a connection between metabolism and immune response. 262 The combination of DHA and butyric acid significantly reduced the methylation of apoptosis related-genes promoters, indicating that the induction of apoptosis by DHA and butyric acid is partially mediated by changes in the methylation status of apoptosis-related genes. 263

Non-coding RNA-mediated regulation of gene silencing is another mechanism of epigenetic regulation of ω-3PUFA, which may interfere with gene expression. Carcinogenic targets of several miRNAs (miRNA-19b, miRNA-26b, and miRNA-203) that are down-regulated by the FO plus pectin diet. 264 ω-3PUFA downregulates miRNA-26 in cholangiocarcinoma cells, and miRNA-26a/b targets 15-hydroxyPGdehydrogenase (15-PGDH) mRNA and inhibits its translation. 15-PGDH can catalyze the oxidation of the 15 (S) -hydroxyl group of prostaglandin E2 (PGE2) which is a pro-inflammatory lipid medium promoting carcinogenesis, so the downregulation of miRNA-26 may be related to the ability of ω-3PUFA to inhibit cancers. 265 Interestingly, ω-3PUFA also directly upregulates 15-PGDH which acts as a tumor suppressor in lung and colon cancer. 266 , 267 Several compounds that can induce 15-PGDH expression have been reported, including histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-γ agonists. Therefore, 15-PGDH can be considered a novel molecular target for cancer chemoprevention and therapy. 268 In addition to affecting miRNA expression, ω-3PUFA also affects its secretion, such as DHA inhibits angiogenesis by triggering exosome secretion of miRNAs which promotes the expression of angiogenic genes in endothelial cells. 269 So, taking full advantage of the anti-cancer effect while inhibiting its cancer-promoting effect of omega-3PUFA may lead to better therapy in cancers, all of which are the main epigenetic modification, and well-known epigenetic markers. 15 Several phase I and phase II clinical trials of omega-3PUFA supplementation in solid tumors have been completed, however, the outcome is ambiguous and requires more precise evidence.

Fatty acid ester of phloridzin

Fatty acid esters of phloridzin significantly inhibit the growth of human hepatocyte HepG2 cells, human breast adenocarcinoma cells, and acute monocyte leukemia cells. It inhibits DNA topoisomerase IIα activity, induces cell cycle arrest in G0/G1 phase and apoptosis by activating caspase-3 and reducing ATP levels and mitochondrial membrane potential in HepG2 cells. The antiproliferative effect of phloridzin DHA ester may be related to the anti-apoptotic gene (BCL2), growth factor receptor (EGFR family, IGF1R/IGF2, PDGFR), and its downstream signaling partners (PI3K/AKT/mTOR, Ras/Raf/MAPK), cell cycle mechanisms like cyclin-dependent kinases (CDK), topoisomerase IIα and IIβ (TOP2A, TOP2B) and down-regulation of epigenetic regulators (HDAC). 270 HDAC plays important role in histone modification, which is also a crucial part of epigenetic regulation in cancer. 271 HDAC inhibitors (HDACi) for cancer treatment are approved by the FDA, 272 which are functional by blocking the catalytic sites of HDACs and changing cellular acetylation patterns, causing the death of cancer cells. 273

Other fatty acid derivatives

Resveratrol (3,4,5-trans-trihydroxystilbene) is a plant antitoxin produced in various plants (such as grapes, peanuts, and cranberries) due to pathogen invasion or other environmental stresses. 274 DMU-214 is a kind of metabolite of cytotoxic resveratrol analog DMU-212, which can regulate several genes related to migration and proliferation (SMAD7, THBS1, IGFBP3, KLF4, Il6, ILA, SOX4, IL15, SRF, RGCC, GPR56) and protein (GPR56, RGCC, SRF, SMAD7, THBS1) 275 to reduce cell proliferation and movement. DMU-214 inhibition of GPR56 expression, the decrease of GPR56 expression triggered by DMU-214 was accompanied by the inhibition of SKOV-3 cell motility. 276 The ginseng metabolite protopanaxadiol (PPD) can induce the expression of BH3-only proteins Puma and Noxa, thereby promoting the death of colorectal cancer cells, and also enhancing the anti-cancer effect of fluorouracil (5-FU). In addition, PPD also induces the expression of autophagy and Bcl2 family apoptosis regulator myeloid cell leukemia-1(MCL-1) that can significantly increase PPD-induced cell death. Interestingly, PPD inhibited the expression of fatty acid and cholesterol biosynthesis-related genes, and induced cancer cell death with fatty acid synthase inhibitor cerulenin. 277 There is no doubt that these metabolites seem to provide an alternative direction for cancer treatment. However, these metabolites regulate gene expression in which ways that needs to be further investigated.

Fatty acids directly affect epigenetics through substrates

Acetyl-CoA establishes an important link between energy metabolism and chromatin regulation. 278 , 279 Fatty acids can affect the level of acetyl-CoA and then directly influence histone acetylation which plays a crucial role in metabolism, signal transduction, and epigenetics. On the one hand, ubiquitous de novo fatty acid synthesis in cancer cells needs to use acetyl-CoA which is provided by the same acetyl-CoA reservoir of histone acetylation. The acetyl-CoA pool is provided by ATP citrate lyase (ACLY) and acetyl-CoA synthase (ACSS). ACLY cleaves citrate into oxaloacetate and acetyl-CoA, ACLY is essential for tumorigenesis in mouse cancer models, and its compound inhibitors with high IC50 values have antitumor efficacy in xenograft models of lung and prostate cancer. However, no active ACLY inhibitors have been reported in vivo tumor models. 106 ACSS links acetate and CoA to produce acetyl-CoA, 280 playing an important role in acetate-dependent tumors. Lacking ACSS2 attenuates tumor burden without any phenotypic defects. Therefore, many ACSS2 inhibitors are needed to be tested in tumor models. 281 , 282 MTB-9655, a kind of small molecule inhibitor of ACSS2, is in phase 1 clinical trial as a potential treatment for patients with cancer (NCT04990739). Reducing the expression of acetyl-CoA carboxylase 1 (ACC1) increases the global histone acetylation and gene expression by reducing FA synthesis, 283 and low-potency ACC1 inhibitor TOFA resulted in tumor regression in MYC-induced renal tumors, 284 at the same time, ND-646, a nanomolar inhibitor of ACC1, inhibits tumor fatty acid synthesis and tumor growth of lung cancer in vivo. 285 , 286 However, no clinical trials about them have been conducted. On the other hand, fatty acid oxidation increases acetyl-CoA levels, leading to an increase in histone acetylation 287 and the expression of lipase and acyl-CoA short-chain synthetase family member 2 (ACSS2). Acetate promotes the expression of lipase and acyl-CoA short-chain synthetase family member 2 (ACSS2). In T cells lacking glucose, acetate promotes histone acetylation, increases IFN-γ production, and promotes tumor clearance. 288 There is evidence that increased histone acetylation can drive increased expression of the transcription factor Twist2 that induces EMT. 289 Overall, inhibiting the fatty acid synthesis and increasing acetyl-CoA levels can promote global histone acetylation which is a potent development prospect for targeted therapy in cancers.

Organic acid

Histones are regulated by many posttranslational modifications (PTMs) 290 and then regulate gene expression at the epigenetic level. There are two specific mechanisms: First, histone PTM changes the net charge of histone molecules or changes the interaction with nucleosomes to adjust the packaging of chromatin directly. Second, histone PTM recruits PTM-specific binding proteins to regulate the structure and function of chromatin. 291 , 292 Histone PTMs play a crucial role in various biological processes such as cell proliferation and differentiation. An abnormal histone modification will cause cancers and other diseases. 293 , 294 In addition to acetyl groups, histone PTM can also reversibly add and cleave other acyl groups (formyl, propionyl, butyryl), myristoyl groups, and dicarboxylic acids (malonate, succinate, pentane). 295 , 296 , 297 , 298 , 299 The studies focus on three kinds of histone modifications: myristoylation of N-terminal glycine residues (N-myristoylation), 300 and the crotonylation (Kcr) form of lysine residues. 298 The fatty acid acylation mechanism of histones directly links fatty acid levels to histone epigenetics (Fig. 3 ), but the specific mechanisms of various organic acids regulating epigenetics and their roles in diseases need to be further investigated. Abnormal epigenetic histone modifications are related to cancer pathogenesis, especially in prognosis and invasiveness of care, which may lead to clinical outcomes. 301 For example, the prognosis in breast cancer is associated with the reduction of lysine acetylation (H3K9ac, H3K18ac, H4K12ac), methylation (H3K4me2, H4K20me3) and arginine methylation (H4R3me2). 302

Epigenetic regulation of fatty acids and their intermediate metabolites in cancer. ACLY cleaves citrate into oxaloacetate and acetyl-CoA, while ACSS connects acetate and CoA to generate acetyl-CoA and generates acetylcholine depot, which together with organic acids affects histone posttranslational modifications and induces Twist2 expression increase. a CRC: SCFAs and ketone bodies inhibit HDAC enzyme to make histone acetylation, up-regulate the tumor suppressor gene, and promote the activation of transcription factors STAT3, NF-kB, FoxP3, N-FAT and RUNX1. It can also directly inhibit the transcription of HDAC gene. ω-3PUFA up-regulates 15 PGDH and catalyzes the oxidation of the 15 (S) -hydroxyl group of prostaglandin E2 (PGE2), fish oil and pectin reduce the pro-apoptotic Bcl2l11, Cideb, Dapk1, Ltbr and Tnfrsf25 promoter methylation which promotes cell apoptosis, and down-regulation of miRNA (miRNA-19b, miRNA-26b and miRNA-203). b BCC: DHA and EPA down-regulate the expression of EZH2, and then H3K27me3 modification. Fish oil can down-regulate the expression of CD44, promote ECM remodeling, and inhibit the migration and invasion of cancer cells. DHA inhibits the PPARγ/NF-κB pathway, blocking MMP-9 expression, and triggers exosome secretion of microRNAs that promote angiogenesis genes to inhibit angiogenesis; phloridzin fatty acid esters inhibit DNA topoisomerase IIa activity and activate caspase, inducing apoptosis, Phloridzin’s DHA ester down-regulates BCL2, growth factor receptor and PI3k/AKT/mTOR, Ras/Raf/MAPK and HDAC

Fatty acids and their derivatives can not only affect the concentration of substrates related to epigenetics but also affect the activities of enzymes related to epigenetics, thereby regulating the expression of genes in epigenetics. This effect is bilateral and can produce both cancer-promoting and cancer-suppressing effects. Whatever, it provides us with a direction: changes in metabolite concentration can affect the level of gene expression, which may be a great way to prevent and cure cancers, even though there is still a long way to go.

Cancer cells show higher metabolic flexibility in responding to metabolic reprogramming, this implies that we are able to increase the intake or production of certain tumor suppressor metabolites to inhibit the process of carcinogenesis and metastasis of cancer. Based on this point of view, many studies have been carried out, such as exogenous intake of fatty acids or intestinal probiotics that produce short-chain fatty acids, 303 , 304 which will be expected to provide powerful methods for tumor prevention and treatment in the future.

Metabolite sensing and epigenetic regulation of protein metabolism

Signal transduction of protein metabolism.

Mammalian target of rapamycin (mTOR)-mediated amino acid sensing is an important metabolite sensing mechanism for amino acids. mTOR itself is a protein kinase. It can detect the abundance of amino acids by working with specific sensor proteins, which mainly are the followings: lysosomal proteins slc38a9 (uncharacterized human member 9 of the solute carrier family 38) 305 and cas-tor1 13 are proven to be metabolite sensor of arginine, Sestrin2 is the leucine sensor, 14 while methyl donor S-adenosylmethionine target of rapamycin (SAMTOR) is a methionine receptor. 306 Meanwhile, a study suggested that map4ke (mitogen-activated protein kinase-3) could also act as an upstream amino acid receptor of mTOR. 307 Leucine synthetase and vacuolar H+-ATPase are two intracellular amino acid sensing elements that are closely related to the activation of mTOR1. When leucine concentration increase, leucine synthase migrates to the lysosome. In lysosomes, leucine synthetase facilitates the proper nucleotide loading of the Rag GTPase heterodimer complex, which stimulates the activity of mTORC1 through the mechanism that will be described later. 308 Vacuolar H+-ATPase is located in the lysosomal membrane and has been identified as a key component of the lysosomal surface amino acid sensing mechanism. It seems to be very sensitive to the accumulation of amino acids in lysosomes. By directly interacting with the regulator-rag complex, it stimulates the activation of mTORC1 when the concentration of amino acids in the lysosome cavity increases. 309

When the cell senses the presence of amino acids, it activates mTORC1. Amino acids recruit mTORC1 on the surface of the lysosome, where the activator Ras (rat sarcoma) homolog enriched in the brain (Rheb), the direct upstream activator of mTORC1, is located. 309 , 310 This recruitment of mTORC1 on the lysosomal membrane is mediated by Rag GTPase heterodimers. 311 , 312 The specific mechanism is that the increased amino acid availability stimulates the transfer of GDP and GTP loading of the Rag heterodimer, 311 which converts Rag GTPase to the active configuration phase, 313 thereby promoting Rag heterodimer to bind to mTORC1 that recruits to the lysosomal surface. 311 Then the “docking” of mTORC1 with lysosomes requires a protein complex called regulators, which provides an anchoring mechanism between the Rag GTPase heterodimer bound to mTORC1 and the lysosomal membrane. In this way, it allows the activation of mTORC1. 310 Interestingly, the study found that when the amino acid adequacy is low, a protein subcomplex called GTPase-activating target of rapamycin 1(GATOR1) has been shown to inactivate the rag heterodimer complex, thereby inhibiting the ability of RAG GTPase heterodimer to recruit mTORC1 on the surface of the enzyme body. 314 When activated, mTOR will phosphorylated p70-S6 kinase 1 (S6K1) and 4E binding protein 1(4E-BP1)), and the phosphorylated S6K1 and 4E-BP1 activate the protein translation initiation complex, then promote protein synthesis. Specially, when 4E-BP1 is phosphorylated, it will promote the release of eukaryotic initiation factor 4E (eIF4E). Therefore, eIF4E is allowed to combine with eIF4G and eIF4A to form the eIF4F translation initiation complex, then activating protein synthesis. 315 At the same time, mTOR can also play a broad regulatory role by phosphorylating other effector proteins. 315 Surprisingly, new research found that glutamine and asparagine activate mTORC1 through a Rag GTPase-independent mechanism that requires ADP-ribosylation factor 1 (Arf1), while leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway as we mentioned before. This research shows mTORC1 is differentially regulated by amino acids through two distinct pathways. 316

Amino acid sensing mediated by mTOR plays an important role in the pathogenesis of tumors. Of all 97 human cancers, mTORC1 is considered to be up-regulated by approximately 70%. 121 It has newly been reported to relate to acute myeloid leukemia, 317 subependymal giant cell astrocytoma, 318 triple-negative breast cancer 319 and pancreatic tumor. 320 mTOR has also been found to be used in the treatment of cancers. So far, two generations of mTOR inhibitors have been developed and have shown promising tumor suppression in preclinical studies. The clinical application of mTOR inhibitors has been successfully tested in treating advanced renal cell carcinoma, neuroendocrine tumors, and HER2-positive breast cancer. 121 It can also ablate cisplatin-resistant salivary gland cancer stem cells, especially combined with platinum-based chemotherapy. 321 Meanwhile, a new study also found that enhance mTOR-targeted cancer therapy can be enhanced by combining of other drugs such as mitoxantrone, an inhibitor of the eukaryotic elongation factor-2 kinase, which is overexpressed in cancer cells and is required for the survival of stressed cells. 322

The amino acid sensing related to G protein-coupled receptor

G protein-coupled receptors are an important metabolite-sensing receptor binder antagonist, and most GPCRs bind to short-chain fatty acids. 118 However, there are a few GPCRs that combine with amino acids and their metabolites, such as tryptophan metabolites nicotinic acid and Kynurenic acid (the host’s intermediate for tryptophan metabolism), and indole-3-aldehyde (derived from tryptophan Bacterial metabolism). 117 Their main function is mainly about adaptive immunity and intestinal barrier that regulates inflammation. GPR109A combines not only with butyrate of short-chain fatty acids but also with niacin, a metabolite of tryptophan. 323 Under physiological conditions, GPR109A can only be activated when the concentration of butyrate is sufficient, and the concentration of niacin is insufficient to activate GPR109A. 138 At the same time, some studies have found that after activating GPR109A by niacin, it can reduce the secretion of proinflammatory cytokines made by macrophages, monocytes and epithelial cells. 324 Meanwhile, recently study found that GPR109A-AKT signaling pathway was related to the butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells. 325 Also, another experience found that supplementation of ketogenic diet with a pharmacological antagonist of the 3HB receptor GPR109A in rats abolished the antitumor effects. 326 Although currently, the researches related to GPR109A’s are mainly focused on its role in inhibiting inflammatory mediators, one research found that it can promote the occurrence of ApcMin/+-driven colon cancer through animal experiments. Adenomatous polyposis (APC) gene mutation is one of the inherited forms of human colon cancer. IL-10 and Treg cells are suppressed after the mutation, and IL-17 promotes Apcmin/mouse (the mouse who has an express point mutation in one copy of APC gene) to develop a colon cancer. However, as for how GPR109A promotes the occurrence of ApcMin/+ driven colon cancer, its specific mechanism needs further study. 115 It is found that colon cancer cells were more sensitive to the depletion of tryptophan compared with normal human colonic epithelial cells. 327

Studies have also found that D-tryptophan and the essential amino acid D-phenylalanine can be combined with GPR109B. GPR109B, like GPR109A, also plays an important role in the immune-free system, but its specific role in tumors is currently unknown. 328 More progress studies of GPR109A in cancer can be seen in the previous fatty acid portion. GPR35 is also related to amino acid metabolites kynurenic acid, lysophosphatidic acid and pamoic acid. It is mainly a GPR that is poorly expressed in the gastrointestinal tract, especially in the small intestine and colon. 329 But its main role is to focus on the onset of colitis, and no research related to malignant tumors has been seen. Study shows the over-expression of GPR137 is associated with the growth of tumor cells, while under-expression of GPR137 has been shown to inhibit cell proliferation in several different types of cancers, but its role in amino acid sensing is still unclear. 330

There are also another kind of GPRs which was combined with protein that related to the tumor development, GPR56. GPR56 binds transglutaminase 2 to suppress tumor metastasis 331 and binds collagen III to regulate cortical development and lamination. 332 GPR56 has shown a high expression level in many cancers, such as esophageal cancer, 333 glioblastoma, 334 human melanoma 335 and colon cancer 276 as a cancer promoting factor which is different from GPR109A and GPR43. Its cancer-promoting effects are related to proliferation, migration, angiogenesis, cell adhesion, apoptosis and cell cycle regulation. 335 , 336 , 337 The expression and activation of GPR56 can regulate the progression of melanoma by specifically inducing IL-6 production after the dissociation of the N-terminal fragment and the self-activation of the C-terminal fragment, thereby promoting cell migration and invasion. 335 The higher level of GPR56 expression in colon cancer patients means a poorer prognosis. The depletion of GPR56 significantly inhibits cell proliferation, migration and invasion. Further research shows that GPR56 overexpression accelerates epithelial-mesenchymal transition by activating PI3K/AKT signaling, promoting colorectal cancer (CRC) cell metastasis. 276 However, GPR56 could inhibit tumor growth and metastasis. 338 Melanoma angiogenesis is inhibited as GPR56 prevents melanoma cells from producing VEGF. It is important in cancer metastasis due to its antagonistic effect with melanoma. 337 There were studies related GPCR to amino acid. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is highly expressed in cancer stem cells. The loss of LGR5 in colon cancer cells enhanced resistance to irinotecan and 5-fluorouracil and increased expression of adhesion GPR56, thus the knockdown of GPR56 in multiple colon cancer cell lines led to suppression of tumor growth and decreased drug resistance, which maybe a new target drug for colon cancer. 339 Considering its dual role, developing target drugs against it is significant. There are already several functional antibodies against GPR56, but they have only been shown to have pharmacological and in vitro activity, and studies in vivo are still lacking, which indicates that functional antibodies are valuable tools for GPCR research. 340 , 341 , 342

The amino acid sensing related to glutamic acid

Glutamic acid, the first metabolite of glutamine, also plays an important role in the development of tumors. It also related to amino acid sensing. Glutamic acid produced by glutamine hydrolysis can be exported from tumor cells through transporters such as recombinant solute carrier family 7, member 11 (SLC7A11 or xCT). Glutamate plays an important role as a signaling molecule in regulating cancer metastasis. The destruction of glutamate cysteine anti-transporter xCT (also known as slc7a11) leads to a retention of cellular glutamate, which makes glutamate fail to function out of the cells, resulting in reduced proliferation and reduced invasion of non-small cell lung cancer. 343 When xCT is functional and glutamate is exported, glutamate can function through multiple types of receptor signals. 344 It can activate MAPK and AKT signaling that promote tumorigenesis by combining with ionic and metabolic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) and gene expression of metabolic glutamate (GRM), thereby reducing intercellular adhesion and increasing tumor erosion. Meanwhile, activity of hypoxia inducible factor-1 (HIF-1), a factor that plays an important role in glycolysis of tumor under hypoxia conditions, is significantly increased by glutamine metabolism. 345

Speak of treatment, many studies have shown that inhibiting xCT has the effect of inhibiting tumor growth, 346 , 347 maybe the potential therapeutic target for tumor. 347 , 348 , 349 Importantly, a recent study showed that xCT inhibition works synergistically with the non-therapeutic agent anti-CTLA-4150. This study laid the foundation for the clinical application of specific xCT inhibitors to expand the efficacy of existing anti-cancer immunotherapy. 350

At present, there is also progress in the research of tumor therapy about glutamic acid. On the one hand, the biological effects of glutamate can be reduced by inhibiting glutamate receptors. Studies have found that reducing gene expression of metabolic glutamate receptor 1 (grm1) through genetic manipulation can proliferate the ER-positive breast cancer cells. 351 In addition, treatment of metabolic glutamate receptor 5 antagonists respectively reduced the metastasis and invasion in vivo and in vitro in oral cancer cell line b88-SDF-1. 352 On the other hand, tumor growth can be directly inhibited by inhibiting glutamine transport. Glutamine is introduced into cells through various transporters, amino-acid transporter 2 (ASCT2) (also known as slc1a5). 353 For example, by reducing the expression of ASCT2 to block glutamine uptake, it leads to a decrease in the proliferation of prostate cancer cells, and activates the mTORC1 signal. 41 Meanwhile, it also reduces the migration of osteosarcoma and triple-negative breast cancer. 354 Another treatment is the use of new 2-amino-4-bis (aryloxybenzyl) aminobutyric acid (aba) derivative drugs designed to target act2, such as v-9302, which has been proven to reduce cell proliferation, increase cell death and oxidative stress. At the same time, v-9302 can also reduce glutamine uptake by preventing excess glutamine transporters’ function, thereby inhibiting the development of cancer. 355 Meanwhile, the study found that glutamate metabolism-related products in the urine of prostate cancer patients were significantly up-regulated, which may have clinical significance for the diagnosis of prostate cancer. 356 L-type amino-acid transporter 1 (LAT1) is also a cancer-associated amino acid transporter gene related to mTOR, which already showed an essential role in the cell proliferation and occurrence of malignant phenotypes. 357 It is also increased in human ovarian cancer cell lines, thus LAT1 may be a target for combination therapy with anti-proliferative aminopeptidase inhibitors to combat ovarian cancer. 358

The metabolite sensing related to downstream amino acid products

Nitric oxide (NO) is a metabolic result of arginine catabolism. According to its time, location and concentration, it has the effect of inhibiting tumor and promoting tumor. 359 It promotes carcinogenesis through a variety of mechanisms, including increasing angiogenesis and limiting the host’s immune response to the tumor. However, it can also be used as a tumor suppressor molecule by activating caspase and inhibiting p53. 359 The study found that 150 nM is the NO concentration threshold: below this concentration, NO stimulates the proliferation of tumor; above this concentration, NO promotes cancer cell death. 360 Especially between 1nM-30nM, NO activates protein kinase G, phosphorylated protein kinase G, whose role is to promote angiogenesis and endothelial cell proliferation, including ERK (extracellular signal-regulated kinase). 360 Between 30 and 100 nM, NO activates other downstream kinases, such as protein kinase b (PKB or AKT), and stimulates proliferation and anti-apoptotic responses in tumor cells. 361 Between 100 and 150 nM, NO stabilizes HIF-1α, thereby increasing the production of vascular endothelial growth factor (VEGF) in endothelial cells and cancer cells, leading to angiogenesis of tumor. 362 , 363 When the concentration of NO exceeds 150 nm, the nitroso stress in the tumor microenvironment increases and the independent stress sensor is activated. In this way, the tumor suppressor gene p53 will be phosphorylated and activated, mitogen-activated protein kinase 1 (MAPK1) will be overexpressed, and cellular respiration will be inhibited, leading to tumor cell apoptosis 363 (Fig. 4 ). Besides, 8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, has an evidenced anti-proliferative activity towards cancer cells. It is found that it can induce changes in protein expression of cell cycle regulators (CDK4, CDK6, cyclin D1, cyclin E) and CDKs inhibitors (p21 Waf1/Cip1, p27 Kip1), then inhibit proliferation and mitochondrial activity in colon cancer HT-29 and LS-180 cells, as well as decrease DNA synthesis. 364 Cadaverine is a downstream product of lysine. Its treatment of breast cancer cell lines corresponding to inhibit cellular movement and invasion, moreover, rendered cells less stem cell-like through reducing mitochondrial oxidation. It is assumed that cadaverine production seems to be a regulator of early breast cancer. 365 All in all, amino acid metabolism has a large difference between normal cells and tumor cells, and this difference has significant clinical significance. For example, the study found that before and after colorectal cancer surgery, amino acid levels such as glycine and arginine have significant differences, which may be used as potential assessment of metabolites for diagnosis of cancer of colon. 366 Besides, it’s demonstrated that the PLS-DA model using the six metabolites (glycine, valine, methionine, citrulline, arginine and C16-carnitine) had a strong ability to identify lung cancer. 367 However, other than the above four pathways, the specific mechanism between these metabolite changes and cancer development needs more research, so as to better provide new tools for clinical diagnosis and treatment (Table 1 ).

The pathways of metabolite sensing of glutamate, leucine and ariginie. It includes three pathways of metabolite sensing of protein. Glutamic acid produced by glutamine hydrolysis can be exported from tumor cells through transporters such as XCT. When Xct is functional and glutamate is exported, glutamate can function through multiple types of receptor signals, thereby reducing intercellular adhesion and increasing tumor erosion. Leucine concentration increasing leads to a migration from leucine to the lysosome, where it facilitates the proper nucleotide loading of the Rag GTPase heterodimer complex, which stimulates the activity of mTORC1. When activated, mTOR will phosphorylate S6K1 and 4E-BP1, and the phosphorylated S6K1 (phosphorylates p70-S6 kinase 1) and 4E-BP1 (4E binding protein 1) activate the protein translation initiation complex, then promote protein synthesis. Arginine can be transported to NO through NOS in cells. Below 150 nm, NO stimulates the proliferation of tumor; above this concentration, NO promotes cancer cell death: When between 1nm-30nm, NO activates protein kinase G, whose role is to promote angiogenesis and endothelial cell proliferation. Between 30 and 100 nm, NO activates other downstream kinases, such as protein kinase B (PKB or AKT), and stimulates proliferation and anti-apoptotic responses in tumor cells. Between 100 and 150 nm, NO stabilizes hif-1α, thereby increasing the production of vascular endothelial growth factor (VEGF in endothelial cells and cancer cells, leading to angiogenesis of tumor. Above 150 nm, the tumor suppressor gene p53 will be phosphorylated and activated, mitogen-activated protein kinase 1 (mkp1) will be overexpressed, and cellular respiration will be inhibited, leading to tumor cell apoptosis

Epigenetics of protein metabolism

Amino acids can directly affect epigenetics through substrates.

The amino acids can affect epigenetics by both by itself or through its substrates. Fox example, intracellular L-arginine is a key regulator of central memory T cell metabolic adaptability, survival ability, and anti-tumor activity through metabolomics and proteomics analysis. Elevated L-arginine levels can cause global metabolic changes, including the transition from glycolysis to oxidative phosphorylation in activated T cells, promote central memory-like cells with higher survival production, and increase antitumor activity in a mouse model. Proteomic analysis showed that T cells were metabolically reprogrammed under the influence of elevated intracellular arginine levels. This experiment further explored the sensors that be needed to mediate arginine metabolism and functional response, and found out three proteins: human bromodomain adjacent to zinc finger domain 1B (BAZ1B), PC4 and SFRS1 (splicing factor, arginine/serine-rich1) interacting protein 1 (PSIP1), and translin (tsn). 368 Human Bromodomain adjacent to zinc finger domain 1B (BAZ1B) is a transcription regulator that contains a prolyl hydroxylase (PHD) domain that binds to methylated histones. PSIP1 is a transcriptional coactivator related to the protection of apoptosis. 369 Currently, there are studies about anti-tumor therapy targeting arginine, and arginase has been shown to play an anti-tumor effect in pre-clinical and clinical settings. 350 , 370

Leucine itself also has an effect on tumorigenesis. The study found that one function of protein leucine residues is to serve as a posttranslational modification site (PTMS), which plays a role in the development of tumors. Studies have determined that the reason why statins can destroy the integrity and invasiveness of tumor cells is partly through the modification of this cysteine (Cys) modification. 371 Also, a recent study suggested that elevation of L-arginine in mice liver cells are the important characteristics of T2DM/NASH-associated hepatocarcinogenesis. 372 Another study confirmed that leucine-rich repeat protein 5 (circFBXL5) is highly expressed in breast cancer tissues and cells, and circFBXL5 knockdown inhibited breast cancer by inhibiting cell migration, invasion and promoting apoptosis. 373 Study also newly indicates that a subset of myeloma identified as an enrichment for basic leucine zipper domain–binding motifs. 374 Meanwhile, depletion of cystine inhibits pancreatic tumor cell growth through the regulation of ferroptotic death. The down regulation of SLC7A could inhibit the tumor growth and induce ferroptotic cell death, which is validated by the application of cystathionineclyase, and provided a theoretical basis for the clinical practice of the ferroptotic cell death-inducing drug. 375

Amino acid derivatives are also involved in epigenetics. Branched-chain amino acids (leucine, isoleucine, and valine) and lysine are decomposed into acetyl-CoA, which may be used by histone acetyl-transferases (HATs). 376 Importantly, the collection of acetyl-CoA from amino acids also regulates protein acetylation and can promote tumor growth. Leucine provides acetyl-CoA to the recombinant E1A binding protein P300 (EP300) acetyltransferase, which mediates inhibitory acetylation of the mTORC1 regulator Raptor at K1097 and leads to mTORC1 activation. 377 As mentioned before, mTORC1 plays an important role in the development of tumors. At the same time, branched-chain amino acids were found to play an important role in the treatment of cancer. BCAA-degrading enzyme branched-chain-amino-acid aminotransferases1 (BCAT1) has become a useful prognostic cancer marker. 378 , 379 , 380 In glioblastoma, BCAA (branched-chain amino acids) catabolism is up-regulated, and this up-regulation depends on BCAT (branched-chain-amino-acid aminotransferases) 381 , 382 indicates that targeting bcat1 treatment may have a good therapeutic window in bcat1 dependent tumor. 383 For example, α-ketoglutarate kills dehydrogenase wild-type glioblastoma cells when BCAT1 protein is lost, which is reversed by re-expression of BCAT1 or supplementation with branched-chain α-ketoacids, downstream metabolic products of BCAT1, which means that the cotreatment of BCAT1 inhibitor gabapentin and AKG results in synthetic lethality. 384 Meanwhile, another new posttranscriptional regulator of BCAT1 expression is identified in chronic myeloid leukemia (CML), the musashi RNA binding protein 2 (MSI2), which coexpressed in CML blast crisis with BCAT1, which means that MSI2–BCAT1 axis is an important mechanism in driving cancer progression in CML. 385

Lysine-derived acetyl-CoA plays an important role in the self-renewal of colorectal cancer tumor initiating cells. CD110 is a hemagglutinin (TPO) reactive homodimeric receptor and is expressed in colon tumor initiating cells. When binding with TPO, CD110 activates lysine degradation, thereby producing acetyl-CoA, which is used for acetylation of low density lipoprotein receptor-related protein6 (LRP6) under EP300 (E1A Binding Protein P300) dependence. LRP6 is a co-receptor for Wingless/Integrated (WNT) signaling and is essential in the renewal of colon tumor initiating cells. The acetylation of LRP6 stimulates the activity of LRP6 and the self-renewal of CD110 colon tumor initiating cells. 386

Amino acid derivative polyamines also can affect tumorigenesis. Polyamines (putrescine, spermine, and spermidine) may be the most famous metabolites that promote tumor proliferation and invasiveness. Increased levels of polyamines have been observed in cancer patients. Polyamines and their metabolites in urine and plasma can be used for cancer diagnosis, and can also be used as a marker of lung cancer and liver tumor progression. 386 , 387 Meanwhile, inhibiting polyamine metabolism can inhibit tumor growth by stimulating anti-tumor immunity. 388 Polyamines affect many processes of tumorigenesis, partly through the regulation of the expression of specific genes through transcription. It acts as charged cations at the pH body and can be associated with nucleic acids, 389 which in turn affects the global chromatin structure and specific DNA-protein interactions, thereby affecting gene transcription. 390 , 391 The posttranscriptional aspects of gene regulation mediated by polyamines are related to eukaryotic translation initiation factor 5A (eFI5A), and its expression/function will adversely affect the prognosis of various cancers. 392 For example, eFI5A is found as one of the differentially expressed proteins in both glioblastoma and neuroblastoma cells. 393 MS13 is one of the curcumin analogs that has the potent cytotoxicity and anti-proliferative effects on human glioblastoma U-87 MG and neuroblastoma SH-SY5Y cells through affecting eFI5A. 393

Moreover, it’s also reported that accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulates the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP-2/9 pathway. This pathway can serve as a potential therapeutic target in nasopharyngeal carcinoma. 394

Amino acids can indirectly regulate enzymes related to epigenetics

The abundance of serine in the body is also related to the occurrence of tumors. 395 For example, study found that serine upregulated in acute myeloid leukemia, 396 as well as primary melanomas. 397 Serine has recently been identified as an allosteric effect factor of M2 isoform of pyruvate kinase (PKM2). 398 PKM2 is often upregulated in cancer and has many carcinogenic effects. 399 For example, by proteomic analysis, it’s demonstrated that PKM2 was identified as key molecules regulated by Wnt/β-catenin signaling in colorectal cancer. 400 Especially in the drug-resistant colorectal cancer, the sponge for the PKM2-targeting miR-122 may be a potential novel therapeutic target. 401 Cisplatin, tamoxifen, and doxorubicin were found to affect tyrosine and alanine in breast cancer cell lines, which may contribute to drug resistance. 402

Serine may link with the metastatic progression of tumor. If serine levels are low, the activity of PKM2 will be reduced, causing glucose-derived carbon to shuttle towards the pathway of serine biosynthesis. However, if the serine level is high, PKM2 is fully active, it will promote a higher rate of glycolysis. 387 This is very important in the development of tumors. PKM2 can be transferred to the nucleus and form a complex with transforming growth factor β signaling inhibitory factor TGFβ-induced factor (TGIF2) and histone deacetylase 3 (HDAC3), and this complex will bind to the cadherin1 (CDH1) promoter and deacetylate it, thereby inhibiting the expression of e-cadherin, so that epithelial cells will lose their mediated cell adhesion and become invasive. 403 Arginine may also play special roles in certain tumor such as melanoma and hepatocellular carcinoma (HCC) through Arg auxotrophy. 404 PEGylated Arg deiminase (ADI-PEG20) breaks down Arg into citrulline and eliminates Arg in the tumor microenvironment, which result in the Arg-auxotrophic tumor cell death, 405 thus ADI-PEG20 serves as a potential target treatment and improves progression-free survival in patients with Arg-auxotrophic mesothelioma. 406

Amino acids can provide metabolic intermediates for epigenetics and then regulate related enzymes. There are many kinds of metabolic intermediates related to tumors, and the current research focuses on these five kinds: acetyl-CoA, SAM, FAD, NAD + and tetrahydrofolate(THF). 407 Among them, S -adenosylmethionine (SAM) is related to the induction of amino acid metabolites. As a methylated methyl donor, methionine is the main amino acid that promotes epigenetic regulation. Both DNA methyltransferase (DNMTs) and histone methyltransferase (HMTs) use SAM as the methyl donor. SAM is produced by methionine adenosine transferase (MAT) using methionine and ATP as substrates in the methionine cycle, 408 which is related to an excess methionine, cysteine, and sulfide in body. 409 After the donor methyl group, SAM becomes s-adenosyl-homocysteine (SAH), meanwhile it inhibits DNMTs and HMTS. Therefore, changes in the SAM/SAH ratio regulate the activity of these methyltransferases. 410 The importance of SAM in tumor survival has been found in various studies, but it is worth noting that the unique requirement of cancer cells for methionine is based on SAM dependence, not methionine dependence. 411 The enhanced methionine cycle leads to an excessive supply of SAM, which leads to DNA hypermethylation and inappropriate gene silencing, as well as abnormal histone methylation and promotion of tumor growth. 412 Threonine dehydrogenase (TDH)-mediated threonine catabolism can also provide precursors for SAM, which means the upregulation of threonine may increase the possibility of tumor development. 413 Besides, it’s found that methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. methionine cycle enzymes are enriched in many tumor types. 414 Although serine is not directly involved in DNA/RNA methylation, serine starvation reduces the DNA/RNA methylation level of cancer cells because of the lack of homocysteine methionine regeneration. 412 Then the subsequent mechanism is described above (Table 2 ). As in the experiment, the restriction of dietary serine and glycine can reduce tumor growth in xenograft and allograft models. 412

As mentioned earlier, amino acids can affect the development of tumors by regulating epigenetics in cells. Through the study of the mechanism, it can better provide new basis for clinical diagnosis and treatment, thereby promoting the progress of tumor diagnosis and treatment. L-asparaginase is a bacteria-derived enzyme that catalyzes the degradation of asparagine into ammonia and aspartate, which plays a important role in leukemia cells. 415 As a result, L-asparaginase is an anticancer agent targeting the amino acid metabolism to treat acute lymphoblastic leukemia (ALL) 416 and extranodal NK/T cell lymphoma. 417

Abnormal cell metabolism has been recognized as a sign of cancer biology. The hallmark of cancer metabolism change is the re-engineering of energy-generating pathways and increased production of biosynthetic intermediates to meet the rapidly proliferating needs of the tumor cells. The dynamic changes of intracellular and extracellular metabolites, especially changes in the concentration of nutrients, can regulate cell signal transduction and gene expression at the epigenetic level through the metabolite sensing mechanism, creating a favorable microenvironment for cancer cells. In this review, we systematically summarize metabolite-sensing mechanism in cancer cells and the signal transduction and epigenetics affected by it and summarize the therapeutic targets for cancers which is related to metabolite sensing as well as the recent advances of target drugs (Table 3 ). It not only further perfects the metabolism and growth mechanism of cancer cells, but also provides a feasible orientation for the research of tumor-targeted drugs, creating a new direction for cancer prevention and treatment.

Future perspectives

In the past few decades, research on the metabolite sensing mechanism has received great attention. In recent years, the metabolite sensing mechanism in cancer has become one of the hot topics, but there are still many problems to be solved. The most thoroughly studied at present is the metabolite-sensitive GPCRs. Their ligands involve three major nutrients as well as their intermediate metabolites. Based on specific functions, metabolite-sensitive GPCRs provide an interesting connection between nutrition, metabolism, gastroenterology, microbiology, and immunology. These receptors provide great potential for understanding how cancer development is closely linked to metabolism. However, previous studies have focused on its role in intestinal immunity and inflammation, while less research has been done in cancers. Is its role in immunity and inflammation related to tumor origination and development? Except in the intestine, do GPCRs play the same role in tumors in other locations? Does metabolite-sensitive GPCR mediate homing and chemotaxis of leukocytes within? Can we develop metabolite-sensing GPCR tool compounds with drug-like properties? Can we adjust the diet to reduce cancer? How can we achieve these? All of the above still need further study. In addition, there is still a large gap for targeted drugs targeting metabolite sensor GPCRs, and their application for cancer therapy is limited due to their bilateral physiological and pathological effects. If these targeted drugs can be spatially targeted to tumors’ space, this will have a huge impact on cancer therapy. At the same time, our review divides cell metabolism into three parts: glucose, fatty acid, and amino acid, in fact, these nutrients share a common metabolic pathway partly. It will be meaningful to find potential therapeutic targets on the common metabolic pathway. In addition, for the current research on fatty acid conjugated sensing mechanism, lipid attachment of proteins involves a variety of lipid types, such as myristate, palmitate, and cholesterol, but the current research focuses on histone modification sites, what is the specific role for histone PTM in the development of tumors? Other than the three major nutrients and their intermediate metabolites, other substances that can affect signal transduction or epigenetics through metabolite sensing mechanisms, such as polyphenols and glucosinolates in the diet. Epidemiology studies have shown that they can effectively reduce the risk of various cancers including prostate cancer and breast cancer, so what is the specific mechanism? Except for these metabolites, are there other substances that can play a role in cancer through metabolite sensing mechanisms? There are a variety of immune cells in the tumor microenvironment, such as macrophages, T cells, etc. How metabolites affect these immune cells and how oncometabolites contribute to tumor immune evasion by affecting the function of immune cells still need to be further summarized. Also, whether the abnormality of metabolite sensors on immune cells affect their function is still unclear. Finally, the kidney has an effective sensing and signal transmission mechanism. The organic anion transporter (OAT) of the 22 family members of the kidney solute carrier can transport various waste solutes and plays an important role in the kidney metabolite sensing mechanism. However, current researches are mostly concentrated on OAT1, so what is the contribution of OAT3 in metabolite sensing and regulation of renal excretion pathways? This may beyond our imagination.

Data availability

Please contact the corresponding author for all data requests.

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Acknowledgements

The authors thank Haosheng Tang for his guidance and suggestions on the figures. The authors thank Wei Zhu for his comments and advices throughout the writing process. We regret that we cannot mention those whose work was not cited because of space limitations.

This work was supported by the National Natural Science Foundation of China [82072594 (Y.T.), 81874139, and 82073097 (S.L.), 81772496, 82073136 (D.X.)], Hunan Provincial Key Area R&D Programs [2019SK2253 and 2021SK2013, Y.T.], and the Central South University Research Programme of Advanced Interdisciplinary Studies [2023QYJC030 (Y.T.)].

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These authors contributed equally: Mengshu You, Zhuolin Xie, Nan Zhang

Authors and Affiliations

Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China

Mengshu You, Zhuolin Xie, Nan Zhang, Yixuan Zhang & Yongguang Tao

NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China

Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China

Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China

Desheng Xiao

Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China

Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People’s Republic of China

Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong

Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, 410011, Changsha, China

Yongguang Tao

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M.Y., Z.X., N.Z., L.L., W.Z., and Y.Z. wrote designed the study and the paper. M.Y. and N.Z. designed and drew figures. Y.T., D.X., and S.L. were the originators of the concept of this paper. All authors have read and approved the article.

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Correspondence to Wei Zhuang , Lili Li or Yongguang Tao .

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The authors declare no competing interests. This manuscript has been read and approved by all authors and is not under consideration for publication elsewhere. Y.T. is the member of editorial board; he has not been involved in the process of the manuscript handling.

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This study was conducted at the Xiangya Hospital, Central South University, Hunan, China. All of the protocols were reviewed and approved by the Joint Ethics Committee of the Central South University Health Authority and performed in accordance with national guidelines.

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You, M., Xie, Z., Zhang, N. et al. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Sig Transduct Target Ther 8 , 196 (2023). https://doi.org/10.1038/s41392-023-01442-3

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Sodhi M , Rezaeianzadeh R , Kezouh A , Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795–1797. doi:10.1001/jama.2023.19574

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Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

1 Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
2 StatExpert Ltd, Laval, Quebec, Canada
3 Department of Ophthalmology and Visual Sciences and Medicine, University of British Columbia, Vancouver, Canada
Medical News & Perspectives As Ozempic’s Popularity Soars, Here’s What to Know About Semaglutide and Weight Loss Melissa Suran, PhD, MSJ JAMA
Special Communication Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists Rasha Alhiary, PharmD; Aaron S. Kesselheim, MD, JD, MPH; Sarah Gabriele, LLM, MBE; Reed F. Beall, PhD; S. Sean Tu, JD, PhD; William B. Feldman, MD, DPhil, MPH JAMA
Medical News & Perspectives What to Know About Wegovy’s Rare but Serious Adverse Effects Kate Ruder, MSJ JAMA
Comment & Response GLP-1 Receptor Agonists and Gastrointestinal Adverse Events—Reply Ramin Rezaeianzadeh, BSc; Mohit Sodhi, MSc; Mahyar Etminan, PharmD, MSc JAMA
Comment & Response GLP-1 Receptor Agonists and Gastrointestinal Adverse Events Karine Suissa, PhD; Sara J. Cromer, MD; Elisabetta Patorno, MD, DrPH JAMA
Research Letter GLP-1 Receptor Agonist Use and Risk of Postoperative Complications Anjali A. Dixit, MD, MPH; Brian T. Bateman, MD, MS; Mary T. Hawn, MD, MPH; Michelle C. Odden, PhD; Eric C. Sun, MD, PhD JAMA
Original Investigation Glucagon-Like Peptide-1 Receptor Agonist Use and Risk of Gallbladder and Biliary Diseases Liyun He, MM; Jialu Wang, MM; Fan Ping, MD; Na Yang, MM; Jingyue Huang, MM; Yuxiu Li, MD; Lingling Xu, MD; Wei Li, MD; Huabing Zhang, MD JAMA Internal Medicine
Research Letter Cholecystitis Associated With the Use of Glucagon-Like Peptide-1 Receptor Agonists Daniel Woronow, MD; Christine Chamberlain, PharmD; Ali Niak, MD; Mark Avigan, MDCM; Monika Houstoun, PharmD, MPH; Cindy Kortepeter, PharmD JAMA Internal Medicine

Glucagon-like peptide 1 (GLP-1) agonists are medications approved for treatment of diabetes that recently have also been used off label for weight loss. 1 Studies have found increased risks of gastrointestinal adverse events (biliary disease, 2 pancreatitis, 3 bowel obstruction, 4 and gastroparesis 5 ) in patients with diabetes. 2 - 5 Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ. Randomized trials examining efficacy of GLP-1 agonists for weight loss were not designed to capture these events 2 due to small sample sizes and short follow-up. We examined gastrointestinal adverse events associated with GLP-1 agonists used for weight loss in a clinical setting.

We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus for Academics database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.

Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors. 6 Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1. Analyses were performed using SAS version 9.4. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.

Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users ( Table 1 ). For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis.

Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR, 9.09 [95% CI, 1.25-66.00]), bowel obstruction (HR, 4.22 [95% CI, 1.02-17.40]), and gastroparesis (HR, 3.67 [95% CI, 1.15-11.90) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]). Exclusion of hyperlipidemia from the analysis did not change the results ( Table 2 ). Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results ( Table 2 ). E-value HRs did not suggest potential confounding by BMI.

This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes. Limitations include that although all GLP-1 agonist users had a record for obesity without diabetes, whether GLP-1 agonists were all used for weight loss is uncertain.

Accepted for Publication: September 11, 2023.

Published Online: October 5, 2023. doi:10.1001/jama.2023.19574

Correction: This article was corrected on December 21, 2023, to update the full name of the database used.

Corresponding Author: Mahyar Etminan, PharmD, MSc, Faculty of Medicine, Departments of Ophthalmology and Visual Sciences and Medicine, The Eye Care Center, University of British Columbia, 2550 Willow St, Room 323, Vancouver, BC V5Z 3N9, Canada ( [email protected] ).

Author Contributions: Dr Etminan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sodhi, Rezaeianzadeh, Etminan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sodhi, Rezaeianzadeh, Etminan.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Kezouh.

Obtained funding: Etminan.

Administrative, technical, or material support: Sodhi.

Supervision: Etminan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by internal research funds from the Department of Ophthalmology and Visual Sciences, University of British Columbia.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement .

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Digestive Disorders
Probiotics: Healthy Bacteria for Your Digestive System

What to Know About Probiotics for Weight Loss

photo of mature woman standing on weight scale

Your body is full of bacteria — but not all of them are bad. Probiotics are friendly bacteria that can be found naturally in fermented foods like yogurt or taken in supplement form. Many people take probiotics to help replenish their guts with good bacteria, especially after taking antibiotics.

Probiotics are necessary for your body to break down food and support a healthy immune system. They may also promote weight loss.

How Your Gut Bacteria Affect Weight Loss

Your gut contains many different bacteria, which are part of your microbiome, a collection of over 100 trillion microbes.

These bacteria all work together to help your body do the following:

Break down nutrients
Break down medications
Protect against disease-causing germs
Keep your gut lining healthy
Influence your immune system‌

Dysbiosis happens when the bacteria in your gut become unbalanced. This can cause digestive problems like irritable bowel syndrome and inflammatory bowel disease , along with allergies and even brain disorders.

But the way bacteria affect your weight is still not fully understood. One study done on sets of twins found that those who were obese had less diversity of gut bacteria compared to those who were lean.

Other studies have discovered that certain bacteria strains may slow down weight gain. Some strains can reduce waist size , while others may help with weight loss. However, some researchers have not been able to find any connection between bacteria and weight.

Most scientists do agree that bacteria affect your metabolism. They do so by helping your body:

Make vitamin K
Make folate (vitamin B9)
Make biotin (vitamin B7)
Make vitamin B12
Absorb magnesium
Absorb calcium
Absorb iron
Break down carbohydrates
Ferment fibers
Make short-chain fatty acids

According to studies done on animals, these short-chain fatty acids can help your body tolerate sugar and use energy more efficiently. They may also help you feel full and suppress your appetite. More research needs to be done to see if these results translate in humans as well.

Do Probiotics Help With Weight Loss?

While good bacteria help you break down nutrients and get energy from your food, there isn’t clear evidence that taking a probiotic supplement or food containing probiotics can help you lose weight. Here's what some studies have found:

Visceral fat wraps around your organs and can affect how your hormones work. It's associated with obesity and leads to insulin resistance and type 2 diabetes . One clinical trial showed that people who have large amounts of visceral fat were able to lose some of this fat after drinking 200 grams of probiotic-containing fermented milk daily for 3 months. ‌

But other trials using specific probiotic supplements show conflicting results. Some probiotic strains were linked to weight loss, while others were not.

Overall, the best probiotics for weight loss may depend on a variety of factors, including:‌

How long you take them
Probiotic type
Your starting weight

Risks of Probiotics for Weight Loss

While probiotics are generally safe, there can be some risks associated with taking them.

Quality . As a food product or supplement, probiotics don’t go through the same rigorous testing as medicines, which means you can’t be sure of the quality of the product you’re buying.‌

Because there are fewer regulations with probiotics, it's hard to tell exactly what you're getting and if the product even has enough bacteria to have any impact on your body. There have also been reports of products that have different strains than what are listed on the label.‌

Bacteria are also living organisms. If the product isn’t made or stored correctly, or is close to its expiration date, the bacteria might not survive long enough to have any beneficial effect on your gut.

Different strains . Probiotic supplements often have different bacteria strains . As mentioned earlier, researchers are still unclear as to which strains may have the most effect on weight loss. This is important to keep in mind if you're taking a probiotic specifically to help you lose weight.

Immune system problems. People who have compromised immune systems or severe diseases can get sick from taking probiotics. You should avoid consuming probiotics if you’re taking medications that suppress your immune system. It's best to talk to your doctor first before taking any probiotic supplement.

In general, while probiotics can have a positive impact on your metabolism, it’s still unclear how or if they can help you lose weight. If you’re concerned with your weight, consult your doctor about diet and lifestyle changes that can help you drop the pounds.

Show Sources

Photo Credit: RyanKing999 / Getty Images

National Health Service (NHS): “Probiotics.”

National Institutes of Health Office of Dietary Supplements: “Probiotics – Health Professional Fact Sheet.”

Nature : “A core gut microbiome in obese and lean twins.”

Nutrients : “Is It Time to Use Probiotics to Prevent or Treat Obesity?,” “Probiotics: How Effective Are They in the Fight against Obesity?”

University of Washington Center for Ecogenetics & Environmental Health: "Fast Facts About The Human Microbiome."

Using Probiotics for Diarrhea

A guide to the best sources and kinds of probiotics to prevent travelers' diarrhea, diarrhea from antibiotics, and more.

Top Foods With Probiotics

See which foods deliver a hefty dose of probiotics, and could be the key to taming your digestive problems.

Are There Health Benefits of Probiotics for Children?

Do children benefit from probiotics? Discover if it is time to incorporate probiotics into your child's routine.

Top Foods High in Probiotics

Learn which probiotic dense foods to eat for better gut health.

Get information about different types of probiotics, their possible health benefits, and how you can simply make them a part of your diet.

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A close-up photo of blue, green and pink pills on a black background. Some of the pills are engraved with names like “Sky.”

Three Studies of MDMA Treatment Retracted by Scientific Journal

The psychedelic treatment, for PTSD, was rejected last week by government regulators.

Doses of MDMA, also known as Ecstasy, in street form. Researchers have been testing the drug as a treatment for PTSD. Credit... Universal History Archive, via Getty Images

Supported by

By Andrew Jacobs

Aug. 12, 2024

The journal Psychopharmacology has retracted three papers about MDMA-assisted therapy based on what the publication said was unethical conduct at one of the study sites where the research took place.

Several of the papers’ authors are affiliated with Lykos Therapeutics, the drug company whose application for MDMA-assisted therapy to treat post-traumatic stress disorder was rejected last week by the Food and Drug Administration.

The company said the research in the retracted papers was not part of its application to the F.D.A.

In declining to approve Lykos’s application, the agency cited concerns about missing data and problems with the way the company’s study was designed, according to a statement released by Lykos on Friday.

The F.D.A. has asked Lykos to conduct an additional clinical trial of its MDMA-assisted therapy, which would have been the first psychedelic medicine to win approval by federal regulators. Lykos has said it would appeal the decision.

The journal retraction was first reported by Stat, the health and medical news website.

On Sunday, Lykos said that it disagreed with Psychopharmacology’s decision and that it would file an official complaint with the Committee on Publication Ethics, a nonprofit that sets guidelines for academic publications.

“The articles remain scientifically sound and present important contributions to the study of potential treatments for PTSD,” the company said in the statement.

The incident cited by Psychopharmacology has been well documented.

In 2015, an unlicensed Canadian therapist who took part in the trial engaged in a sexual relationship with a participant after the conclusion of the trial’s dosing sessions.

In civil court documents , the patient, Meaghan Buisson, said she was sexually assaulted by the therapist, Richard Yensen, who at the time was working alongside his wife, a licensed therapist.

Mr. Yensen has said the relationship was consensual and initiated by Ms. Buisson. Six months after the final session, she moved from Vancouver to Cortes Island, in British Columbia, where the couple lived, according to court documents .

The relationship between patient and practitioner continued for more than a year, the documents said. Professional associations in both Canada and the United States prohibit sexual relationships between psychologists and patients for at least two years after their final session.

The incident helped highlight some of the challenges associated with psychedelic medicine, which can render patients especially vulnerable during dosing sessions.

For that reason, most clinical trials involving psychedelic compounds require the presence of two mental health professionals. (Lykos’s trials with MDMA require only one of the practitioners to be licensed.)

The Multidisciplinary Association for Psychedelic Studies, or MAPS, is the nonprofit that carried out the research and later created Lykos to market its proprietary MDMA-assisted therapy. The association publicly acknowledged the incident in 2019, adding that it had been reported to the F.D.A. and to Canadian health authorities.

The company acknowledged on Sunday that it had failed to notify Psychopharmacology about the violations, but it said that the oversight should have been addressed through a correction, not a retraction.

Andrew Jacobs is a Times reporter focused on how healthcare policy, politics and corporate interests affect people’s lives. More about Andrew Jacobs

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New research developments and insights from Metabolism

Olivia m. farr.

1 Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA

2 Section of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA

Michelle Camp

Christos s. mantzoros.

In a field of great importance to daily life and clinical care, metabolic-related research covers a wealth of information and knowledge. This broad field encompasses a number of physical states that are increasingly critical to study, including obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Additionally, the impacts of diet, nutrition, and exercise on these physical states are an area of ever-important and expanding research. With the latest advances in metabolic research, much knowledge has been gained. Here, we present the newest findings from research published in Metabolism. We hope that these results provide not only critical knowledge needed for clinical care and daily life, but also a platform for the continuing expansion of research into metabolic-related issues.

Diet and Nutrition

Carbohydrate influences on body composition in polycystic ovary syndrome.

In order to target healthy weight loss, diet composition may require special consideration for women with poly-cystic ovary syndrome. Goss et al. ( 1 ) demonstrated in a crossover study of 30 women with poly-cystic ovary syndrome (aged 31 ± 5.8 years) that consumption of a reduced-carbohydrate diet as compared to a standard diet significantly decreased the amount of adipose tissue without changing total calories consumed over the course of eight weeks. While on the low carbohydrate diet, loss of fat mass occurred from subcutaneous-abdominal, intra-abdominal, and thigh-intermuscular adipose tissues (−4.6%, −7.1%, and −11.5%, respectively). Furthermore, the reduced-carbohydrate diets were also associated with decreased insulin levels. In contrast, the “standard” diet may have decreased lean mass by converting it to fat. Therefore, women with polycystic ovary syndrome who consume a diet lower in carbohydrates may preferentially lose fat mass from unhealthy areas of the body. Future studies could be focused on whether altering fat or protein content has a similar effect on the loss of fat mass in women with polycystic ovary syndrome.

Impacts of ginsenosides on hyperlipidemia and GLP-1

Ginsenosides, found in Panax Ginseng, help to ameliorate hyperlipidemia, but the mechanism by which they act is still not yet completely understood. Liu et al. ( 2 ) investigated whether glucagon-like peptide-1 (GLP-1) release mediated by ginseng total saponins (GTS), in addition to exerting anti-diabetic properties, have effects on hyperlipidemia in 20 obese male Sprague-Dawley rats (weighing 100g–200g). After the rats were randomized to receive either a high-fat diet (HFD) intervention or a chow control diet for four weeks, rats on the HFD were further randomized to a treatment of low-dose (150 mg/kg/day) or high-dose (300 mg/kg/day) GTS for an additional four weeks. Liver weight in rats fed a HFD decreased by 6.8% and 7.8% after the low- and high-dose treatments, respectively. As measures of body fat content, epididymal fat and retroperitoneal fat decreased 21% and 16%, respectively, in rats treated with high-dose GTS as compared to HFD control rats. Similarly, plasma levels of triglycerides, total cholesterol, and free fatty acids decreased by 39%, 15% and 16%, respectively, with high-dose treatment. Lastly, plasma levels of Apo-B48 and LDL-C decreased by about 38% and 28%, respectively, again with high-dose GTS treatment. Moreover, treatment with ginsenosides improved insulin resistance and leptin sensitivity and increased GLP-1 levels. Although it was determined that oral ginsenosides may mediate the anti-hyperlipidemic effects through greater GLP-1 secretion, future research should consider whether oral ginsenosides may have a direct effect on lowering lipid profiles.

Vitamin D influences diabetic outcomes

Vitamin D deficiency often accompanies type 2 diabetes, but the potential role of vitamin D in the pathogenesis of diabetes, if any, remains unclear. Kampmann et al. ( 3 ) sought to determine whether administration of vitamin D in 16 subjects with type 2 diabetes who had a vitamin D deficiency would positively affect insulin and inflammatory markers. In a randomized double-blind trial with 16 participants, 8 adults (aged 61.6 ± 4.4 years) received oral cholecalciferol (280 μg/day for two weeks and 140 μg/day the following 10 weeks) and 8 additional adults (aged 57 ± 4.5 years) were given placebo. Plasma 25-hydroxyvitamin D (25OHD) significantly increased 238% (p=0.01) in the supplemented group, whereas 25OHD decreased 7.8% in the placebo group (p=0.02). Serum-1,25 (OH) 2 also increased by about 40% in the treatment group. C-peptide levels, incremental AUC insulin and insulin secretory burst mass showed a trend towards improvement, which, however, did not reach the level of statistical significance (p = 0.05 – 0.10), indicating a potential improvement in insulin secretion. Insulin sensitivity and inflammation, however, did not improve with vitamin D replacement therapy. Future research with larger sample sizes and longer treatment duration could help elucidate further benefits of vitamin D supplements for type 2 diabetes.

Fish-based diets and endothelial function

To test whether a fish-based diet with high n-3 polyunsaturated fatty acids (>3.0 g/day) may improve endothelial function as compared to a control diet, Kondo et al. ( 4 ) enrolled 23 postmenopausal women with type 2 diabetes (aged 69.7 ± 6.6 years) in a randomized, crossover trial to consume either the fish-based or control diet for 4 weeks followed by the opposite for the next four weeks. Determinants of endothelial function improved with the fish-based diet: peak forearm blood flow by 63.7%, duration of reactive hyperemia by 27.9% and flow debt repayment by 70.7%. While the fish-based diet as compared to the control diet resulted in improvements in endothelial function, these observations did not correlate with n-3 polyunsaturated fatty acid levels, suggesting that something else in the fish diet may be causing these improvements. Future studies should examine this in more general populations, as well as more broadly seek to discover the beneficial component in the fish-based diet.

High protein diets influences on hormones

Henning et al. ( 5 ) sought to determine whether a diet high in protein during an energy deficit may attenuate the typically observed fat-free mass loss through insulin-like growth factor 1 (IGF-1) signaling. Using a block-randomized design, 33 adult participants were assigned to a diet with protein levels of either the recommended daily allowance (RDA) (aged: 22 ± 1 years), twice the RDA (aged: 21 ± 1 years) or three times the RDA (aged: 22 ± 1 years; 0.8, 1.6, or 2.4 g/kg/day, respectively) for 31 days. Hormone levels were measured and compared after 10 days of a weight-maintaining diet and 21 days later after a 40% energy-deficient diet. Energy deficit decreased IGF-1 levels (14%) and testosterone levels (total: 16%, free: 23%) and increased IGF binding proteins (63%), regardless of protein level intake. Changes in these molecules did not correlate with changes in fat-free mass seen after energy deficit, suggesting that they may not play a role in mediating the relationships between energy-deficient diets and fat-free mass regardless of high protein intake. Future studies should examine other potential mechanisms to prevent loss of fat-free mass during energy deficient diets.

Influences of maternal diet on insulin resistance in the offspring

To determine whether a mother’s HFD during pregnancy or lactation would affect insulin resistance in their offspring, Melo et al. ( 6 ) examined newborn or recently weaned mice (6 animals per litter) from ten mothers who were randomly assigned to receive a HFD or control diet. Recently weaned (28 days old), but not newborn mice (0 days old), showed elevated markers for endoplasmic reticulum stress and triglycerides. Thus, these results suggest that maternal diet may have more influence over offspring metabolic dysfunction during lactation rather than pregnancy. Future studies should examine how this may continue into adulthood risk of obesity and metabolic comorbidities.

Balanced high fat diets improve cardiometabolic risk

Silver et al. ( 7 ) hypothesized that a balanced high fat diet (9g/day) for 16 weeks, containing equal amounts of saturated, monounsaturated, and polyunsaturated fats, would lessen cardiovascular disease risk and inflammation. The 144 obese, premenopausal women (aged 36.7 ± 6.8 years) stabilized on the HFD for 2 weeks were subsequently randomized to supplement their diet with either encapsulated stearate (18:0), oleate(18:1), linoleate (18:2) or placebo for 12 weeks. Body fat mass decreased by about 2.5 ± 2.1% while lean mass increased by about 2.5 ± 2.1%. Additionally, multiple inflammatory marker levels decreased in all groups. HFD supplemented with stearate most effectively reduced the inflammatory marker interferon gamma by 74%, while HFD supplemented with linoleate most markedly decreased plasminogen activator inhibitor-1, a measure of vascular function, by 31%. These results may suggest that balancing fats would improve cardiovascular disease risk in women. However, future studies should expand these results by testing the effects on broader populations, including men and postmenopausal women, and studying any potential long-term effects

Walnuts may help improve metabolic risk factors

In a controlled crossover study comparing a walnut-enriched diet to a control diet, Wu et al. ( 8 ) examined whether walnuts may improve biomarkers for metabolic risk, including lipids, inflammatory markers, and adipokines. Forty participants (aged 60±1 years) were randomized to consume either a walnut-enriched diet (43 g/day) followed by a control diet or the reverse order, each for a period of 8 weeks. Consumption of a walnut-rich diet, placebo-adjusted, resulted in a 4.7% decrease in non-HDL cholesterol levels and a 5.4% decrease in apolipoprotein-B levels, findings that may implicate how walnuts help to reduce cardiovascular disease risk. Other markers of metabolic dysfunction such as insulin resistance, inflammatory markers, and adipokines were not affected. Future research should further define the relationship between walnut consumption and cardiovascular risk as well as determine the long-term impacts of a walnut-enriched diet on heart health.

Coffee and green tea consumption on diabetes risk

To determine if coffee or green tea may influence biomarkers of diabetes, Pham et al. ( 9 ) collected data through cross-sectional epidemiological surveys from 1440 Japanese participants aged 18–69 years. In overweight participants only, higher coffee consumption was associated with a significant decrease in insulin resistance as measured by homeostatic model assessment of insulin resistance (HOMA-IR; p for trend =0.03), while green tea consumption surprisingly was associated with an increase in HOMA-IR (p for trend = 0.02). Neither coffee nor green tea consumption was associated with glycated hemoglobin (HbA1c) levels. This study may suggest other benefits of coffee with regards to diabetes risk, though this would need to be confirmed in future, placebo-controlled studies. Additionally, the difference in caffeine between coffee and green tea may have influenced the results and future research should determine if caffeine is a potential factor contributing to associations with insulin resistance.

Western vs. Mediterranean diets’ influence on inflammatory markers

Whether and how healthy or unhealthy Western or Mediterranean diet patterns may influence inflammatory biomarkers and adipokines is not yet clear. Therefore, Park et al. ( 10 ) examined in 151 participants (aged >37 years) whether these markers may be associated with healthy Western and Mediterranean diets through food frequency questionnaires and cross-sectional associations among dietary parameters. C-reactive protein, an inflammatory marker, was negatively correlated (p<0.001) with “healthy” versions of both diets even when possible confounders were controlled, suggesting increased inflammation with poorer diets. Irisin was not associated with healthy versions of these diets, although it was correlated with body mass index (BMI; p=0.008), waist circumference (p=0.003), and fat mass (p=0.01), which often result from poor diets. Future research should confirm whether and how irisin may interact with long-term diets to influence obesity.

Caloric restriction does not influence cortisol levels

To determine the role of weight loss in overweight individuals on cortisol levels, Tam et al. ( 11 ) implemented 24-week 25% calorie restriction with or without exercise in 35 otherwise healthy overweight adults (aged 38.1 ± 5.8 years) as compared to a control group of 11 participants (aged 38.5 ± 7.4 years) who were assigned to a weight maintenance diet. While diet changes overall caused 10% weight loss without impacting cortisol levels, decreased insulin sensitivity was correlated with elevated morning (p<0.004) and diurnal (p<0.02) cortisol levels. Future studies need to determine whether changes in insulin sensitivity may indirectly cause the changes in cortisol with weight loss in obesity and whether other aspects of weight loss, such as exercise, may also play a role in cortisol changes.

Mediterranean diets, without weight loss, do not influence adipokines

To determine how a Mediterranean diet may impact adipokine levels for individuals with metabolic syndrome, Richard et al. ( 12 ) examined 26 men between 24 and 62 years of age with metabolic syndrome. Participants consumed a North American diet for 5 weeks and then a Mediterranean diet for 5 weeks- both under isocaloric conditions, which they then followed with a 20-week caloric restriction period of weight loss and then a 5-week Mediterranean diet, again under isocaloric conditions. The Mediterranean diet prior to caloric restriction or weight loss did not impact leptin, resistin, adiponectin, or plasminogen activator inhibitor-1, but after caloric restriction and weight loss, it decreased both leptin by 32.1% and increased adiponectin by 14% compared with the control diet and by 30.4% and 12.9% respectively as compared to the Mediterranean diet before caloric restriction. Thus, without weight loss, a Mediterranean diet does not appear to impact most adipokines for individuals with metabolic syndrome. Future controlled studies should delve further into the usefulness and benefits of weight loss with a Mediterranean diet.

Coffee influences insulin and glucose levels

A common morning beverage, it is unclear how caffeinated coffee may alter blood sugar responses. Thus, Gavrieli et al. ( 13 ) conducted a randomized, controlled, cross-over study in 33 adults aged 19–44 years, of which 17 were overweight/obese and 16 were female, to determine how caffeinated coffee may impact postprandial glucose and insulin concentrations. The participants consumed coffee/placebo under three conditions of 200mL water, coffee containing 3mg/kg body weight caffeine, or coffee containing 6 mg/kg body weight caffeine. Coffee increased the area under the curve for glucose by 8.1% at the 3mg/kg caffeine level and by 11.4% at the 6mg/kg level. Coffee further delayed the rise of insulin in response to a standardized meal, suggesting that coffee may have effects on glucose/insulin that may impact the development of diabetes. Interestingly, these effects differed by gender and BMI, suggesting that women/men and obese/lean patients may respond differently to caffeinated coffee. Notably, these effects were short-lived and coffee only had a temporary effect on these outcomes. Future studies are needed to determine gender-specific mechanisms as well as whether coffee and/or caffeine contribute to these effects.

Effects of a short-term high fat diet and acute glucose ingestion on AMPK signaling

AMP-activated protein kinase (AMPK), which senses energy and regulates metabolism, may be affected by consumption of a HFD. As immune peripheral blood mononuclear cells (PBMCs) are often activated by high-fat diets, Wan et al. ( 14 ) sought to determine in these cells the short-term dietary impact on AMPK and the mitochondrial oxidative phosphorylation (OXPHOS) proteins. Using nine healthy male adults (aged 21 ± 3 years) who participated in a seven-day HFD intervention, they were able to assess glucose tolerance with an oral glucose tolerance test (OGTT) as well as phosphorylation and circulating cytokines before and after the intervention. The results confirmed the hypothesis that AMPK signaling would decrease with a HFD. AMPK phosphorylation was even lower two hours later after OGTT when compared to following OGTT before the HFD. OXPHOS protein expression also was not affected. With the role that AMPK dysregulation may play in the pathogenesis of metabolic diseases, the study of PBMCs may allow for future studies to assess possible dietary effects on AMPK and inflammatory signaling.

Sodium intake and overweight

Song et al. ( 15 ) cross-sectionally examined the relationship between sodium intake and weight amongst 5955 participants (aged 19–64 years) who gave detailed dietary information. While men did show an increased risk of being overweight with higher sodium intake at an odds ratio of 1.37 and 1.67 for the fourth and fifth quintile of weight as compared to the lowest quintile, women showed only a marginally significant trend towards this same risk with an odds ratio of 1.31 from the highest as compared to the lowest quintile. Thus, this study suggests that increased sodium intake may relate to increased weight in adults, particularly in men. Future, well-controlled clinical trials would be needed to confirm these findings.

Flaxseed and olive oil offer same benefits to inflammation

Both olive oil and flaxseed oil appear to have anti-inflammatory effects, although they have different fat composition, and it is unclear whether one may have greater anti-inflammatory effects than the other. Kontogianni et al. ( 16 ) compared the effects of flaxseed and olive oil on lipid and inflammatory markers in a cross-over, randomized study of 37 normal weight, healthy young adults (aged 25.6 ± 5.9 years) who typically adhered to a Mediterranean diet pattern. Flaxseed and olive oil showed no differences in adiponectin, tumor necrosis factor-α, CRP, lipid levels or glucose. However, they did show reduction in total by about 5% and low-density lipoprotein by about 6.7% cholesterol levels with both oils from baseline. Thus, while both oils are beneficial, there appear to be no significant differences in inflammatory or lipid benefits between olive or flaxseed oil. Future studies may wish to examine these oils in other dietary patterns, as well as in comparison to other common oils, such as vegetable or canola oil.

Effects of fish or fish oil on adiponectin

Whether a food item or supplements of the desired ingredient may have the same effect is a common question. Neale et al. ( 17 ) used a randomized trial to examine whether total or high molecular weight adiponectin may be changed in 29 overweight and obese participants who underwent four weeks of isocaloric dietary changes with either 1.8 g fish or fish oil supplement. High molecular weight adiponectin was significantly increased by about 8% in the group which consumed more fish, whereas it decreased by about 17% in the group which was given supplements. This study may indicate that the effects of fish on adiponectin are regulated by more than fish oil itself, and thus, that the supplements do not impart the same benefit. Future studies may seek to identify which is this beneficial component of fish.

Effects of different types of caloric restriction on insulin signaling

Wang et al. ( 18 ) set out to determine the differential effects of caloric restriction based on carbohydrate or fat restriction on body composition and insulin sensitivity. They performed euglycemic-hyperinsulinemic clamps and skeletal muscle biopsies of 18 obese individuals (20–45 years old) without diabetes after 5 days of a eucaloric diet, 5 days of a high fat/low carbohydrate diet, or 5 days of a low fat/high carbohydrate diet. While being on a 30% calorie restricted diet of either low fat/high carbohydrate or high fat/low carbohydrate did not differentially effect weight loss or whole-body insulin sensitivity, the low fat/high carbohydrate diet improved skeletal muscle insulin signaling in a way that would eventually improve insulin sensitivity by increased phosphorylation of IRS-1 tyrosine by about 60% and decreased phosphorylation of IRS-1 Ser307 by about 30%, while the high fat/low carbohydrate diet led to opposite changes that may lead to insulin resistance by increasing phosphorylation of IRS-1 Ser307 by around 100% and decreasing IRS-1 associated p110 by about 25%. Thus, the type of caloric restriction in dieting may be significant to change overall insulin sensitivity.

Diet alone impacts cardiometabolic risk

To better define the relationships between exercise, insulin resistance, and lipid accumulation, Rinnankoski-Tuikka et al. ( 19 ) examined in a controlled study high fat and low fat diets in 58 male C57BL/6J mice who were active or sedentary for 19 weeks. Another group of 30 mice, who were initially fed the HFD and were sedentary for 9 weeks, were then switched to a low fat diet while assigned to be sedentary or active for the remaining 10 weeks. The HFD increased triglycerides in muscle tissue by about 55%. Switching to the low fat diet reversed these changes, and exercise- whether they were assigned to be sedentary or active- did not impact these effects. These results need to be repeated and confirmed in humans and the role of exercise in regulating insulin sensitivity and lipid accumulation better defined.

Impacts of diet on fertility and reproductive function

Adipose tissue has clear implications on female reproductive functions and fertility. In order to determine how obesity may impact ovarian follicle development, Wang et al. ( 20 ) examined with a controlled, randomized trial. 36 female rats (12 weeks old) who were fed a control, calorie restricted or HFD for 18 weeks. Those on the HFD showed less primordial follicles, decreased by about 49%, and increased atretic follicles, by about 25%, with increased levels of mTOR pathway proteins by about 40% and decreased levels of SIRT1 signaling proteins by about 25%. The calorie restricted rats showed the opposite pattern with increased primordial follicles by about 44% and decreased atretic follicles by about 16%, while mTOR signaling proteins decreased by about 20% and SIRT1 increased by about 30%. These results might indicate evidence of changes that are associated with early puberty and infertility during obesity, as seen with the HFD, while calorie restricted rats show changes associated with the opposite pattern of delayed puberty and prolonged fertility. Additionally, better understanding of how mTOR and SIRT1 influence these effects may lead to effective therapies to combat reproductive consequences of obesity.

Exercise impacts cardiometabolic function in type 2 diabetes

Since type 2 diabetes can complicate cardiovascular health, there is a clear need to identify effective therapeutic strategies to slow non-ischemic subclinical left-ventricular (LV) dysfunction disease progression towards heart failure. Thus, Sacre et al. ( 21 ) examined in a controlled, randomized clinical trial if a six-month exercise intervention would improve peak oxygen uptake (VO 2 peak) and cardiac autonomic function in 49 subjects with type 2 diabetes and subclinical heart disease as compared to the standard of care (25 participants aged 60 ± 9 years in the control condition and 24 participants aged 59 ± 10 years in the exercise condition). The exercise intervention increased VO 2 peak by 11% and decreased resting heart rate by about 3%, indicating some significant improvements. Although myocardial fibrosis may have abated with physical activity, LV function failed to improve. Exercise training, therefore, has the ability to ameliorate exercise intolerance and improve some cardiovascular functions in these patients. Alterations to the current exercise design, whether in duration, intensity, or complementary therapies, could potentially shed more light on further benefits of exercise training in type 2 diabetic patients with subclinical LV dysfunction.

Effects of acute or chronic exercise on irisin levels

To test the differences between acute and chronic exercise on irisin levels, Huh et al. ( 22 ) examined irisin levels in 14 females (aged 24.3 ± 2.6 years) before, after 6 weeks of long-term whole-body vibration exercise training following an acute session of exercise, and outside of exercise but after 6 weeks of training. Irisin was significantly elevated immediately following the acute bought of exercise at 6 weeks (by about 91%), but did not increase at the end of 6 weeks. This suggests that exercise consistently elevates irisin levels without changing baseline levels with chronic exercise. Future studies may want to examine other types of exercise for similar changes.

KLAKS improves cardiometabolic risk

To evaluate the success of Concept Leipzig: Adiposity therapy for school aged children (KLAKS), a one-year exercise-based lifestyle program for overweight/obese children, Bluher et al. ( 23 ) examined metabolic and anthropometric outcomes of 115 overweight or obese children (BMI greater than the 90 th percentile between the ages of 7 and 18) who participated in KLAKS. Indeed, KLAKS decreased metabolic risk factors, including body fat by about 11%, BMI by about 6%, and HbA1c by about 5%, suggesting decreased risk of obesity and diabetes for children who participated in the KLAKS program. Future studies may examine how this program would influence other metabolic comorbidities of obesity, including cardiovascular disease risk.

Impacts of exercise breaks on long sedentary periods

When sedentary behavior is uninterrupted, it may increase insulin resistance and glucose intolerance. Saunders et al. ( 24 ) sought to determine in a cross-over, interventional study if periodic light walking and/or moderate physical activity would improve these parameters in 19 children and adolescents (8 females; aged 10–14 years). All subjects participated in three conditions of 8 hours of sitting, 8 hours of sitting with 2 minute walking breaks every 20 minutes, and 8 hours of sitting with 2 minute walking breaks and two 20-minute moderate physical activity breaks. They found that breaking up a long sedentary period with either light walking or light walking and moderate exercise does not change the effects of a long sedentary period on insulin, glucose, or lipids. These results may suggest that other solutions would be needed to combat metabolic problems resulting from long periods of sedation. Future studies may want to test longer-term impacts of these different scenarios as well as other options for improving the impacts of long sedentary periods.

Exercise mitigates some metabolic effects of a high fat diet

Since exercise improves postprandial glucose and insulin, Numao et al. ( 25 ) tested whether this effect may be impacted by a high-fat diet, which typically impairs postprandial glucose and insulin. Thus, they performed a randomized, cross-over study in 11 healthy men (aged 27 ± 1 years) with 3 three-day interventions of a normal diet, a HFD, and a HFD with a single exercise session on the third day. They found that this single session of exercise did not reverse the impairment in postprandial glucose and insulin caused by a high-fat diet. On the other hand, exercise did normalize GLP-1, which had been increased by the high-fat diet. This study suggests that exercise may mitigate some but not all of the metabolic impairments caused by a high-fat diet. Future studies may seek to discover if these effects are further improved by longer or multiple exercise sessions.

Irisin increases hippocampal neuronal growth at pharmacological doses

Moon et al. ( 26 ) studied how irisin, a novel myokine, might influence hippocampal neurogenesis in vitro with H19-7 cell lines. Pharmacological (50–100nmol/L), but not physiological (5–10 nmol/L), concentrations increased cell proliferation by 70–80% and signal transducer and activator of transcription 3 (STAT3) activation by 100% as compared to control. However, neither physiological nor pharmacological concentrations altered other markers of neurogenesis, including microtubule-associated protein 2 or synapsin. These data suggest that irisin may have limited effects on hippocampal neurogenesis. Future studies may want to investigate how irisin may behave in vivo and whether it may have effects on memory at pharmacological doses.

Circulating irisin increases in response to exercise in pigs

In order to determine if exercise might increase FNDC5 mRNA and protein, or plasma irisin in pigs, Fain et al. ( 27 ) examined muscle and adipose tissue from castrated male Rapacz familial hypercholesterolemic (n=13; 10–11 months of age) and Yucatan miniature (n=16; 10–12 months of age) pigs after 16–20 weeks of exercise to look for these key markers using reverse transcription polymerase chain reaction and western blotting techniques in a cross-sectional study. They did not find increases in FNDC5 mRNA or protein in the muscle or adipose tissue of either of the pigs. However, circulating irisin, as measured by ELISA, was increased in these animals by 42% after exercise. Thus, the authors hypothesize that exercise in pigs may not be as good of a model as mice. Future research may want to investigate how/why the circulating irisin is elevated without changes in FNDC5 mRNA.

Novel findings in type 2 diabetes and insulin sensitivity

Dpp4 treatment effects on inflammation.

Sitagliptin, a drug used in treatment of diabetes mellitus type 2, selectively inhibits dipeptidyl peptidase-4 (DPP4), a precursor of GLP-1. With the increasing presence of inflammation and endothelial dysfunction in atherosclerosis, which is often associated with type 2 diabetes, it is imperative to examine potential drug benefits with anti-inflammatory capabilities. Tremblay et al. ( 28 ) performed a double-blind, cross-over, placebo-controlled study in 36 adults with type 2 diabetes (aged 58.1 ± 6.4 years) using 100 mg/day of sitagliptin or placebo for a 6-week period with a 4 week washout between phases. They discovered that sitagliptin significantly decreased inflammatory biomarkers such as CRP by 44.9%, interleukin (IL)-6 by 24.7% and IL-8 by 7.8%. Additionally, the increase in GLP-1 inversely correlated with the decrease in CRP (p<0.01). These improvements may indicate potential future usefulness of sitagliptin in managing other metabolic diseases. Future studies may want to test the usefulness of sitagliptin therapy on cardiovascular disease and obesity.

Influences of estrogen and testosterone on insulin sensitivity

Exposure to high levels of testosterone or estrogen in skeletal muscle has been found to decrease insulin sensitivity. To better understand how these hormones may influence insulin sensitivity, Garrido et al.( 29 ) examined whether acute skeletal myotube exposure in vitro to supraphysiological doses of either estradiol or testosterone (concentrations for both: 0, 10nM, 100nM, 1μM, 10μM) directly affected glucose metabolism. Skeletal biopsies for cell culture were obtained from 19 healthy volunteers (9 male; aged 42 ± 4 years). Both 10μM estrogen and testosterone decreased glucose metabolism as represented by glucose transitioning to glycogen by 39 and 54% respectively as compared to a control case in the presence of 60nM insulin. Furthermore, this effect was dependent on protein kinase C (PKC) activation, and indeed, estradiol and testosterone caused a 41% and 106% increase, respectively, in phosphorylation of PKC. Since the PKC signaling pathways appear to be influenced by the aforementioned hormones, future studies should focus on the differing PKC isoforms to determine the exact mechanism through which each hormone regulates glucose metabolism and how these steroids may interact with glucose metabolism at physiological doses.

Epigenetic changes relating to obesity and type 2 diabetes

Epigenetic changes relating to immune function as it operates within obesity and type 2 diabetes in not yet clear. In order to better understand how DNA methylation may be changed in obesity and diabetes, Simar et al. ( 30 ) collected cross-sectional data from 44 male patients. Of those, 14 were obese, non-diabetics (aged 35.1 ± 6.7 years), 11 were age-matched lean (aged 34.8 ± 3.0 years), 12 were type 2 diabetics (aged 44.1 ± 6.5 years) and 8 were age-matched lean (aged 44.1 ± 6.0 years). Obesity and type 2 diabetes demonstrated increased methylation in B and natural killer cells of up to double the methylation, which increased with increasing insulin resistance as measured by HOMA-IR (p<0.009). Thus, it appears that epigenetic changes in lymphocytes may relate to changes in inflammation and immune cell function observed in obesity and diabetes. Future studies may seek to determine the directionality and underlying mechanisms of these changes.

Epigenetic effects of a diabetic intrauterine environment

To examine the role of DNA methylation in diabetes risk, del Rosario et al. ( 31 ) examined leukocytes from Pima Indian adolescents whose mothers had (14 participants; aged 15.5 ± 5.1 years) or didn’t have (14 participants; aged 16.2 ± 5.8 years) diabetes during pregnancy. DNA methylation was found to be different in the two groups for promoters of maturity onset diabetes of the young (MODY; hsa04950) and Notch signaling pathways (hsa04330). Thus, these changes may in fact increase risk for type 2 diabetes. Future studies should further investigate whether these epigenetic changes do in fact lead to later in life type 2 diabetes.

Polymorphisms of the adiponectin gene in relation to microvascular complications among diabetics

In order to determine if polymorphisms of the adiponectin gene may influence microvascular complications in type 2 diabetes, Choe et al. ( 32 ) genotyped 708 patients with type 2 diabetes and compared this with incidence of diabetic nephropathy, which was defined as urine albumin/creatinine ratio (UACR) greater than 30 mg/g. Even when controlling for other possible confounders, the GG genotype at rs2241766 for the adiponectin gene was significantly associated with diabetic nephropathy with an odds ratio of 1.96 but not retinopathy or neuropathy, implicating this polymorphism with the specific risk for diabetic nephropathy. Thus, patients with type 2 diabetes and the GG genotype at rs2241766 should be carefully monitored for diabetic nephropathy. Future studies may want to better define the role of this gene in diabetic nephropathy.

Independent effects of diabetes and aging on incretins

By examining middle-aged as compared to older individuals with and without type 2 diabetes, Geloneze et al. ( 33 ) attempted to determine whether and how diabetes and aging may interact to alter insulin sensitivity and incretins. They examined cross-sectionally 25 middle-aged participants (aged 45 ± 3 years), of which 13 had type 2 diabetes, as compared to 25 older adults (aged 65 ± 2 years), of which 13 had diabetes. Both middle-aged and older adults with diabetes had decreased insulin sensitivity index (ISI) by about 70% as compared to non-diabetics. GLP-1 was reduced in the older diabetics at p<0.05. These results may show an increased impact of aging with diabetes on incretins (GLP-1), but this will need to be confirmed in future studies.

Effects of estrogen on insulin sensitivity

How obesity and estrogen deficits may interact to impact insulin sensitivity in the brain is not yet clear, although obesity alone reduces insulin sensitivity and estrogen therapy may improve these deficits. Pratchayasakul et al. ( 34 ) examined how 30 female rats (about 6–7 weeks old) given a 12 week HFD or control diet, who did or did not receive ovariectomies, were impacted by subsequent 50 μg/kg estrogen replacement or placebo therapy from week 13 for 30 days. All ovariectimized rats had impaired insulin sensitivity as measured by HOMA index, but only rats that ate the control diet showed improved insulin sensitivity with estrogen replacement back to control levels. Thus, there may be a greater impact of combined obesity and estrogen deprivation on insulin sensitivity that will need to be further defined and more effective treatments identified.

Inflammatory effects of obesity impacting insulin sensitivity

While many obese individuals develop type 2 diabetes, others do not. To determine differences in inflammation that may underlie these differences, van Beek et al. ( 35 ) compared obese women who had diabetes (28 participants; aged 51 ± 7 years) or were insulin-sensitive (26 participants; aged 48 ± 6 years) to 12 lean controls (aged 50 ± 5 years). As predicted, those who were both obese and diabetic showed higher levels of inflammatory markers, including IL-6 (increased by about 283% in insulin-sensitive obese as compared to lean and by about 556% in diabetic obese as compared to lean), increased leukocytes by about 18% in obese diabetics as compared to insulin-sensitive, and increased circulating T cells by about 40% in obese diabetics as compared to insulin-sensitive obese. These results suggest that inflammation may underlie the changes from insulin sensitive to resistant obesity, though this will need to be confirmed with other studies and more in-depth experiments.

Effects of insulin sensitivity/resistance on sleep

Although pre-diabetes, type 2 diabetes and obesity have been associated with short sleep duration, how insulin resistance may impact sleep is unclear. Liu et al. ( 36 ) examined cross-sectionally by self-report how much obese individuals who were insulin-sensitive (21 participants; 8 men; aged 55 ± 9 years) or insulin-resistant (35 participants; 15 men; aged 56 ± 9 years), but not diabetic, reported sleeping on average, where under seven hours per night was considered to be of short duration. Indeed, they confirmed that insulin-resistant obese individuals had shortened sleep duration by about 10% as compared to the insulin-sensitive obese individuals, despite no differences in BMI or waist circumference. The authors conclude that there is an independent association between insulin resistance and shortened sleep duration without diabetes. Future, controlled studies should be done to confirm these findings.

Diabetes and prediabetes have important impacts on coronary flow reserve

Coronary flow reserve can be used to establish the existence of coronary artery disease. Erdogan et al. ( 37 ) sought to compare coronary flow reserve in 65 prediabetics (aged 51.4 ± 8.6 years) to that in 45 individuals with (aged 51.6 ± 7.2 years) or 43 individuals without (aged 50.4 ± 8.5 years) diabetes in order to determine risk for coronary artery disease. Coronary flow reserve was lowest in individuals with diabetes, at about 22% of individuals without diabetes, but still lower in prediabetics than controls by about 13%, even though age, gender, and smoking status were matched across groups. Additionally, coronary flow reserve inversely correlated with age (p<0.04), fasting glucose levels (p<0.001), and HbA1c levels (p<0.001), suggesting a potential association between coronary flow reserve and diabetes. Thus, this study suggests that prediabetics should also be monitored for coronary artery disease. Future, longitudinal and prospective studies should confirm these findings.

Biomarkers for cardiometabolic dysfunction

Cytokines associated with cardiometabolic risk.

With much yet to be determined about the cytokines irisin and omentin-1, Panagiotou et al. ( 38 ) aimed to investigate if these markers may be associated with cardiovascular risk and lipoprotein subparticles. The effect of alcohol consumption on these markers was examined in 39 subjects with either diabetes or two other cardiovascular risk factors cross-sectionally at baseline, 3 months and 6 months. Repeated measures from baseline to 6 months exhibited an inverse correlation between decreasing irisin and increasing omentin-1 with a 7.4% irisin decrease per 1-standard deviation increment in omentin-1. In addition, after adjusting for age, sex and race, a decrease in irisin was observed with increasing high density lipoprotein (HDL) levels with a 7.3% decrease per a 10mg/dL increment. Omentin-1 and mean very low density lipoproteins (VLDL) size were positively associated with a 3.8% increase in omentin-1 per a 1-SD increment of VLDL. Both cytokines show promise as cardiovascular risk markers. Due to potential irisin resistance findings in those at risk for metabolic syndrome, future studies are warranted both for possible irisin sensitizers such as omentin-1, as well as for aims to explore if a direct mechanism exists between irisin and omentin-1.

Relationship between adiponectin and stroke

Whether adiponectin may play a role in stroke is unclear. To better clarify if and how adiponectin may interact with ischemic stroke, Kuwashiro et al. ( 39 ) studied adiponectin levels from 171 patients (115 male; aged 68.3 ± 10.1 years) and 171 matched controls (115 male; aged 68.1 ± 10.1 years) at stroke onset and at 3, 7, 14, and 90 days following. Overall, at stroke onset, adiponectin did not significantly vary between all stroke patients and controls, although it was lower for patients with atherothrombotic infarction by about 29% and higher in patients with cardioembolic infarction by about 39%. Adiponectin levels at stroke onset were higher in patients with poorer functional outcomes by about 43%. These results may indicate some relationships between adiponectin and stroke, particularly certain subtypes, but this will need to be confirmed and explored in future studies.

Actions of adiponectin in inflamed adipose tissue

To better understand the role of adiponectin in adipocytes, Nakatsuji et al. ( 40 ) set out to determine whether adiponectin was present in adipose tissue from male lean (wild type) or obese (db/db) mice (n= 4–6, each group). Adiponectin was present in adipose mature adipocyte and stromal vascular tissues and was higher in obese as compared to lean mice by about 300–400%. When adiponectin was given to mice that were knock-outs for adiponectin, adiponectin collected in adipose tissue, particularly when obese. This study suggests that adiponectin may selectively accumulate in adipose tissues during obesity. Further research should look into mechanisms and whether and how this may relate to observed decreased overall levels of adiponectin in obesity.

Adioponectin may improve adipose tissue vascularity in obesity

Aprahamian ( 41 ) examined how adiponection-deficient (apn-KO) and over-expressing (apn-TG) mice reacted to a chow or high fat/high sucrose diet for 32 weeks starting at 8 weeks of age as compared to wild type in order to determine how adiponectin may influence the adipose tissue microenvironment. Over-expression of adiponectin increased vascularity and perfusion of adipose tissue by about 200% as measured by staining with green for vasculature and measuring the luminosity which indicated capillary density. Adiponectin deficient mice did not show poorer perfusion or function and with the high fat/high sucrose diet, they did not show impaired insulin resistance or hepatic steatosis as compared to wild type. Aprahamian concludes that increased adiponectin may improve conditions of obesity by increasing adipose tissue vascularity and perfusion. The signaling pathways involved should be elucidated to better demonstrate how adiponectin may influence/improve obesity-related inflammation.

Markers of liver function also mark metabolic health

To examine how markers of liver function related to overall metabolic health, Liu et al. ( 42 ) examined data from a cross-sectional study of 616 randomly enrolled participants (aged 18.3 ± 0.02 years) and prospective cohort of 93 subjects who came back 2 years later. Cross-sectionally, alanine transaminase (ALT) and gamma-glutamyltransferase (GGT) were correlated with cardiometabolic outcomes including heart rate, systolic and diastolic blood pressure, cholesterol, high density lipoproteins, low density lipoproteins, triglycerides, and dyslipidemia, while fetuin-A was correlated with insulin, insulin resistance, and blood pressure. In the prospective arm, ALT and GGT were found to predict anthropometric outcomes at 2 years with multivariable linear regression models. These results may suggest that traditional liver markers, such as ALT and GGT, would be important to monitor for resultant overall metabolic health. Future studies should confirm and expand on these findings.

Irisin may be a marker for fatty liver disease

In order to determine whether irisin levels may be a marker of fatty liver, Polyzos et al. ( 43 ) cross-sectionally examined irisin levels in 31 patients (aged 53.9 ± 2.9 years) with biopsy-confirmed simple steatosis or steatohepatitis (NASH) as compared to 24 lean (aged 54.2 ± 1.6 years) and 28 obese (aged 52.6 ± 1.6 years) controls without non-alcoholic fatty liver disease (NAFLD). Irisin levels were decreased with obesity by about 32% as compared to lean controls and both simple steatosis by about 39% and NASH by about 28% as compared to lean adults, which remained after adjustment for BMI, gender, age, exercise, and insulin resistance. Irisin was also associated with portal inflammation as irisin was about 20% higher in those with portal inflammation. Thus, there appears to be links between irisin levels and fatty liver, though these will need to be confirmed with future clinical studies.

Irisin as a novel marker for future insulin resistance

In order to determine if irisin may mediate the relationship between weight regain after loss and insulin resistance, Crujeiras et al. ( 44 ) examined irisin levels in 136 obese participants (62 women; aged 43.0 ± 11.2 years) who had undergone an eight-week weight loss program of 30% reduced energy. Irisin levels were measured just before starting the program, immediately following the program, and after a four to six month follow-up period, during which half had regained weight. Increased insulin resistance, measured by HOMA-IR, at follow-up was associated with elevated irisin levels at baseline, before the weight loss program (p<0.05). This finding may suggest that irisin could be a marker for insulin resistance upon weight regain. The mechanisms which may mediate this association need to be delineated in future studies.

Irisin mediates energy expenditure in a subset of humans

In order to determine whether responsiveness to irisin may mediate differences in energy expenditure, Swick et al. ( 45 ) monitored irisin levels over the course of a day in 17 postmenopausal women between 50 and 70 years of age as they were sedentary and consumed standardized meals. Irisin levels did not overall vary with individual requirements, although in a subset of participants whose energy expenditure was greater than what would be expected based on fat free mass, irisin levels, but not leptin or adiponectin, were correlated with energy expenditure over the course of the day (p<0.0016). Therefore, it appears that there are individual differences in responsiveness to irisin that may modulate its effects. Future studies should delve further into these potential relationships in larger, controlled trials.

Leptin does not influence fetuin-A, a marker of fatty liver

Since fetuin-A appears to be important in fatty liver diseases, Hwang et al. ( 46 ) hypothesized that fetuin-A levels may be mediated by leptin. In a series of experiments examining fetuin-A levels with hypoleptinemic adults who were given metreleptin therapy, they attempted to parcel apart this relationship. The first substudy contained 15 lean adults (8 men aged 23.3±1.2 years and 7 women aged 23.7±1.5 years) and was a placebo-controlled, cross-over study with metreleptin therapy given at doses of 0.04 mg/kg/day for men and 0.08 mg/kg/day for women on day 1 which was increased for days 2–3 to 0.1 mg/kg/day for men and 0.2 mg/kg/day for women. Measurements were obtained on day 1 and day 4 in the morning. The second substudy involved seven lean women (aged 25.0±2.2 years) who participated in an open label clinical trial of metreletin at doses of 0.08 mg/kg/day for 2 months and then 0.2 mg/kg/day for a third month. Measurements were taken one month before starting the study and after 1, 3, 7, and 11 weeks of therapy. The third substudy involved 17 lean, hypoleptinemic women (aged 26.1±3.9 years), who participated in a randomized, placebo-controlled trial of metreleptin at doses of 0.08 mg/kg/day for 12 weeks and then an increase to 0.12 mg/kg/day if they had not yet responded. If weight decreased by more than 5%, the metreleptin dose was decreased to 0.04 mg/kg/day. Measurements were taken before and after 12, 24, and 36 weeks of therapy. The fourth substudy was an in vitro study using human hepatoma HepG2 cells that were treated with 0, 5, 10, 20, and 100 ng/mL leptin and then underwent real time PCR to examine them for fetuin-A mRNA expression. Fetuin-A was not moderated by caloric deprivation or metreleptin therapy in hypoleptinemia. Leptin given to cells did not modify fetuin-A mRNA expression. Therefore, it appears that leptin does not influence fetuin-A levels. Future studies may seek to determine whether and how fetuin-A modulates fatty liver disease outcomes.

Leptin improves mitochondrial function and hepatic steatosis in obese mice

In order to determine how leptin influences mitochondrial function, Holmstrom et al. ( 47 ) treated obese and lean mice (aged 14–20 weeks) with daily 0.9 % saline or 1 mg/kg body weight of leptin intraperitoneal injections for 5 days before extracting liver and muscle tissues to assess mitochondrial respiration. Obese mice showed decreased liver mitochondrial respiration by about 30% and increased muscle mitochondrial respiration by about 35%, but this was corrected to control levels with leptin treatment. Leptin treatment in ob/ob mice also decreased liver weight by 32% as well as triglyceride content by 31%. These findings suggest that leptin positively impacts mitochondrial function and hepatic outcomes in obesity. Future, controlled studies in humans should be performed to determine if leptin therapy may also show beneficial effects on hepatic and mitochondrial outcomes.

Impact of leptin on the immune system

In a recent in vitro study, Cassano et al.( 48 ) revealed that leptin directly regulates T cell autophagy using human CD4(+)CD25(−) conventional T cells. During T cell receptor (TCR) stimulation, in vitro treatment with leptin inhibited autophagy through the mTOR pathway, and this inhibition depended on both duration and dosage. This finding was further confirmed in leptin-deficient mice that had higher than normal levels of autophagy. These results have important implications on leptin’s role in nutritional status and immune activation, and these relationships should be explored more in the future.

Adipokines in relation to myelodysplastic syndrome risk

In order to determine how adipokines may relate to myelodysplastic syndrome, Dalmaga et al. ( 49 ) implemented a case-control study on 101 individuals with myelodysplastic syndrome (58–83 years old; 59 males) and 101 age- and gender-matched (57–83 years old; 59 males) control participants. The risk of myelodysplastic syndrome was associated with increased fetuin-A by about 10%, decreased adiponectin by about 28%, and decreased leptin by about 8%, even when controlled for demographic and social variables, BMI, and insulin. These links should be better defined and a potential causal role between these adipokines and myelodysplastic syndrome should be investigated.

Chemerin is not associated with acute coronary syndrome

Coronary artery disease severity correlates with levels of the novel adipokine, chemerin, suggesting that this could be an indicator of heart disease. Aronis et al. ( 50 ) sought to discover if chemerin also predicts acute coronary syndrome. In a cross-sectional study of 90 men whose serum was collected 2 years prior to acute coronary syndrome and 162 matched controls (aged 66.3±9.6 years). Chemerin was unable to predict acute coronary syndrome, suggesting that chemerin may not serve as a general marker of heart disease though it may play a role in more chronic heart disease. Future studies should parcel apart this relationship and determine what role chemerin may play in relation to coronary artery disease.

FGF21 in human brown adipose tissue

In order to discover whether fibroblast growth factor 21 (FGF21) may target human brown adipose tissue, Hondares et al. ( 51 ) examined cross-sectional FGF21 gene expression in induced brown adipose tissue from nine adults with pheochromocytoma, ten adult controls, and 18 newborns (20–40 gestational weeks) who had died between 1995–2006 and were autopsied 2–3 hours after death. FGF21 mRNA was expressed in brown adipose tissue from infants (median 6.9 × 10 −8 ) and adults with pheochromocytoma (median 3.3 ×10 −8 ), but not control adult white adipose tissue, suggesting that FGF21 targets brown adipose tissue. Future studies should determine the role FGF21 may play in interacting with brown adipose tissues.

Cardiometabolic risk factors and interventions

Impact of weight loss surgery on metabolic comorbidities in adolescents.

Although weight loss surgery improves outcomes in adults, whether these bariatric surgeries may also improve metabolic comorbidities in adolescents remains to be discovered. Oberbach et al. ( 52 ) piloted a study in 10 obese adolescents (9.7–19.7 years of age) who underwent either laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y-gastric bypass bariatric surgery as compared to 17 normal-weight, age-and gender-matched adolescents (12.5–16.5 years of age) pre- and 12 months post-operatively. They discovered that after a year, risk factors for metabolic comorbidities, including diabetes (HOMA-IR decreased 51.9%), cardiovascular disease (systolic blood pressure decreased 6.8%, high density lipoproteins increased 21.4%), and liver function tests (alanine aminotransferase decreased 43.9%), were all improved. This study suggests that bariatric surgery may be sufficient to improve metabolic comorbidities in obese adolescents, though this will need to be confirmed with future studies.

Childhood adversities influence cardiometabolic risk in midlife

To examine how overall childhood adversity may confer obesity later in life, Davis et al. ( 53 ) performed a cross-sectional analysis of data from 210 midlife adults (aged 45.8 ± 3.3 years). Overall childhood adversity, which combined the number, severity, and chronicity of adversities during childhood, was a significant predictor of central obesity as measured by waist-hip ratio with multivariate linear regressions, but not BMI. Thus, this study suggests that overall childhood adversity may represent a unique metabolic risk in the form of central obesity in midlife. These findings may have implications of healthcare as these individuals may be further at risk for other metabolic dysfunctions, though this will need to be confirmed by future studies.

Stress during adolescence impacts metabolic risk differentially by gender

Stress causes changes in weight that can lead to obesity, but it is not clear exactly how these changes may occur. Krolow et al. ( 54 ) assessed with a randomized, placebo-controlled study how isolation stress during adolescence (beginning on postnatal day 21 until 28) may alter diet, weight gain, and hormones in both male and female Wistar rats. Rats were divided into four groups of which 31 controls received lab chow, 36 controls received palatable diets, 36 isolated animals received lab chow, and the remaining 36 isolated animals received palatable diets. After postnatal day 28, rats were returned to normal cage groupings and fed standard lab chow. In both females and males, isolation stress led to increased consumption of a palatable diet at levels up to double the kcal of the chow diet under the same isolation stress and at levels more than the kcal consumed of the palatable diet in control situations. In females, this also increased weight gain by about 30% over the chow in the same stress situation, adiponectin by about 77% over the palatable diet in control situations, and triacylglyceride levels by 66% over the palatable diet in control situations. In males, stress increased hypothalamic neuropeptide Y levels by up to 467% over the rats who were not exposed to stress. Although in females, these effects disappeared in adulthood, males had increased weight over time after exposure to the palatable diet over the chow diet during stress and decreased adiponectin by about 20% over the control group who had also received the palatable diet. Thus, these findings demonstrated differential effects of stress in adolescence with females showing short-term feeding effects and males showing longer-term effects in adulthood. Future research should endeavor to identify potential mechanisms underlying these changes.

Timing of menarche may predict risk of metabolic syndrome

In order to find more predictors for the risk of metabolic syndrome, Glueck et al. ( 55 ) conducted a 26-year prospective follow-up study of 272 girls (aged 5–22 years at first study and 30–46 years at follow-up) to determine how early (≤10 years) and late (≥16 years) menarche may impact the risk of adult metabolic syndrome. Early menarche was associated with high childhood BMI (21.2 ±1.0 kg/m 2 ) and increased risk of both childhood (15%) and adult (36%) metabolic syndrome. Late menarche was associated with low childhood BMI (18.1±1.0 kg/m 2 ) and increased incidence of adult metabolic syndrome (47%). Metabolic syndrome in adulthood was also associated with early-late menarche, showing a u-shaped relationship. Thus, girls who have early or late menarche should be monitored carefully into adulthood for metabolic syndrome. Future studies may seek to investigate further potential causal relationships between early or late menarche with obesity and metabolic syndrome.

Methionine restriction decreases risk of hepatic steatosis in obesity

Malloy et al. ( 56 ) conducted a randomized, placebo-controlled trial to investigate how a 14-week dietary methionine restriction (0.12% methionine) might decrease hepatic steatosis in 10-week-old obese ob/ob mice as compared to a control diet (0.86% methionine). Methionine restriction reduced body weight by about 18%, decreased liver triglycerides by about 50%, decreased insulin and HOMA-IR by about 50%, reduced the gene expression of inflammatory markers such as tumor necrosis factor-α by about 46% and CCR2 by about 44%, increased very low density lipoprotein secretions by about 20%, and increased adiponection levels by about 129%. Therefore, the authors concluded that methionine restriction may decrease steatosis by increasing lipid export and reducing inflammatory responses to obesity. Future randomized, controlled trials should be conducted in humans to confirm these findings.

GLP-1 therapies may decrease cardiometabolic risks

GLP-1 analogues have gained attention for their effective treatment of diabetes and obesity, although they may also have important cardioprotective effects as well. Aronis et al. ( 57 ) evaluated GLP-1 effects (escalating doses at 50–2000 nmol/L) on angiogenesis in vitro with human umbilical vein endothelial cells, and discovered that GLP-1 does increase angiogenesis from 200 nmol/L to 1000 nmol/L with an inverted u-shaped dose response curve and the optimal dose being at 500 nmol/L. Treating the system with inhibitors for Akt, PKC, or src pathways decreased the effects of GLP-1 on angiogenesis, suggesting that its cardiovascular effects are mediated through these pathways. Future research should better delineate these pathways and interactions.

New techniques

Non-invasive mri technique to study brown adipose tissue.

In an effort to develop a new technique to classify brown as compared to white adipose tissue, Holstila et al. ( 58 ) compared the usual positron emission tomography (PET) with 18-fluorodeoxyglucocose ( 18 FDG-PET) technique with a new dual echo spectral presaturation inversion recovery (DUAL-SPIR) magnetic resonance imaging (MRI) scan with eleven male Sprague-Dawley rats (weighing 325–400g). The new DUAL-SPIR MRI was more accurate, meaning a better correlation, in comparison to histological findings (p<.017) than the standard PET technique (p<.078) and can be applied to human subjects. The DUAL-SPIR MRI under normal temperature conditions was also feasibility tested in one male and two female normal-weight human subjects as compared to the traditional PET method after cold exposure. DUAL-SPIR MRI measured 51, 32, and 53 g of brown adipose tissue in each of the cases, while PET measured 54, 46, and 16 g respectively for each of the cases. Therefore, there is potential for a non-invasive method to more accurately measure brown adipose tissue in humans using this type of MRI. Future, larger human studies should confirm these preliminary findings.

New MRI techniques to examine hepatic steatosis

In order to test a method for early detection of hepatic steatosis, d’Assignies et al. ( 59 ) examined how multi-echo MRI, MR spectroscopy (MRS), and histology ex vivo post-mortem may be able to detect steatosis in 32 rats (13 8-week-old Wistar, 6 26-week-old Wistar and 13 diabetic, 8-week-old Goto-Kakizaki rats) who were given a 72-hour intravenous infusion of glucose and intralipid fat emulsion or saline. MRI and MRS detected liver steatosis showed greater sensitivity while maintaining accuracy (sensitivity of 92.9% vs. 50% in histology and area under the ROC curve of 0.841 vs. 0.641 for histology) of which rats received the glucose and intralipid infusion as compared to placebo. The amount of fat shown in these imaging techniques correlated with insulin and c-peptide levels (all p<.01). Thus, these non-invasive magnetic resonance techniques for imaging should be tested both in vivo in rats to ensure that these ex vivo results are reproducible in vivo and then in humans to see if they may also be effective at early detection of liver steatosis.

Uptake of 18-fluorodeoxyglucose assessed by CT and PET imaging to assess brown adipose tissue is not altered by hypoglycemia

Since there is an association between hypoglycemia and both increased heat production and hypothermia, Schopman et al. ( 60 ) sought to determine if brown adipose tissue, which is activated by cold exposure and stimulated by the sympathetic nervous system, was also affected by hypoglycemia. Using PET and computer tomography to measure the uptake of labeled glucose analogue 18 F-fluorodeoxyglucose ( 18 FDG-PET) in brown adipose tissue due to thermogenesis, they examined in nine healthy adults (aged 19–30 years old) the effect of hypoglycemia (blood glucose 2.5 mmol/L) versus euglycemia (4.5 mmol/L) on brown fat. Under conditions of mild cold exposure (17°C), it was concluded there was no differential effect of hypoglycemia on brown adipose tissue as compared to normal blood glucose levels. Future studies should determine a clearer relationship between hypoglycemia and increased energy expenditure, and which potential factors could be responsible.

Conclusions

While the field of metabolic-related research continues to grow and expand, we have gained much knowledge and insight into impacts of diet, exercise, biomarkers, risk factors, and potential new techniques to be employed in the future. These new insights have important effects on both clinical care and daily life, which is part of what makes metabolic-related research a critically growing field. Additionally, this wealth of new information will be a key foundation from which future research may continue to expand and grow.

Acknowledgments

Funding: NIH 5T32HD052961

Olivia M. Farr is supported by a NICHD 5T32HD052961.

Abbreviations

GLP-1	glucagon-like peptide 1
25OHD	25-hydroxyvitamin D
RDA	recommended daily allowance
IGF-1	insulin-like growth factor 1
HDL	high density lipoprotein
HOMA-IR	homeostatic model assessment of insulin resistance
HbA1c	glycated hemoglobin
HFD	high fat diet
BMI	body mass index
AMPK	AMP-activated protein kinase
PBMCs	peripheral blood mononuclear cells
OXPHOS	oxidative phosphorylation
OGTT	oral glucose tolerance test
LV	left ventricular
VO peak	peak oxygen uptake
KLAKS	Concept Leipzig: Adiposity therapy for school aged children
STAT3	signal transducer and activator of transcription 3
DPP-4	dipeptidyl peptidase-4
IL	interleukin
PKC	protein kinase C
MODY	maturity onset diabetes of the young
ISI	insulin sensitivity index
VLDL	very low density lipoproteins
ALT	alanine transaminase
GGT	gamma-glutamyl transferase
NAFLD	non-alcoholic fatty liver disease
NASH	non-alcoholic steatohepatitis
TCR	T cell receptor
FGF21	fibroblast growth factor 21
PET	positron emission tomography
DUAL-SPIR	dual echo spectral presaturation inversion recovery
MRI	magnetic resonance imaging
MRS	magnetic resonance spectroscopy

Disclosure Statement: The authors have nothing to disclose.

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