1 3155 100 GLUTAMINE METABOLISM IN ADIPOCYTES: A BONA FIDE EPIGENETIC MODULATOR OF INFLAMMATION. A CHRONIC LOW-GRADE INFLAMMATION OF WHITE ADIPOSE TISSUE (WAT) IS ONE OF THE HALLMARKS OF OBESITY AND IS PROPOSED TO CONTRIBUTE TO INSULIN RESISTANCE AND TYPE 2 DIABETES. DESPITE THIS, THE CAUSAL MECHANISMS UNDERLYING WAT INFLAMMATION REMAIN UNCLEAR. BASED ON METABOLOMIC ANALYSES OF HUMAN WAT, PETRUS ET AL. SHOWED THAT THE AMINO ACID GLUTAMINE WAS THE MOST MARKEDLY REDUCED POLAR METABOLITE IN THE OBESE STATE. REDUCED GLUTAMINE LEVELS IN ADIPOCYTES INDUCE AN INCREASE OF URIDINE DIPHOSPHATE N-ACETYLGLUCOSAMINE (UDP-GLCNAC) LEVELS VIA INDUCTION OF GLYCOLYSIS AND THE HEXOSAMINE BIOSYNTHETIC PATHWAYS. THIS PROMOTES NUCLEAR O-GLCNACYLATION, A POSTTRANSLATIONAL MODIFICATION THAT ACTIVATES THE TRANSCRIPTION OF PRO-INFLAMMATORY GENES. CONVERSELY, GLUTAMINE SUPPLEMENTATION IN VITRO AND IN VIVO, REVERSED THESE EFFECTS. ALTOGETHER, DYSREGULATION OF INTRACELLULAR GLUTAMINE METABOLISM IN WAT ESTABLISHES AN EPIGENETIC LINK BETWEEN ADIPOCYTES AND INFLAMMATION. THIS COMMENTARY DISCUSSES THESE FINDINGS AND THEIR POSSIBLY THERAPEUTIC RELEVANCE IN RELATION TO INSULIN RESISTANCE AND TYPE 2 DIABETES. 2020 2 6203 20 THE INFLUENCE OF EPIGENETIC MODIFICATIONS ON METABOLIC CHANGES IN WHITE ADIPOSE TISSUE AND LIVER AND THEIR POTENTIAL IMPACT IN EXERCISE. BACKGROUND: EPIGENETIC MARKS ARE RESPONSIVE TO A WIDE VARIETY OF ENVIRONMENTAL STIMULI AND SERVE AS IMPORTANT MEDIATORS FOR GENE TRANSCRIPTION. A NUMBER OF CHROMATIN MODIFYING ENZYMES ORCHESTRATE EPIGENETIC RESPONSES TO ENVIRONMENTAL STIMULI, WITH A GROWING BODY OF RESEARCH EXAMINING HOW CHANGES IN METABOLIC SUBSTRATES OR CO-FACTORS ALTER EPIGENETIC MODIFICATIONS. SCOPE OF REVIEW: HERE, WE PROVIDE A SYSTEMATIC REVIEW OF EXISTING EVIDENCE OF METABOLISM-RELATED EPIGENETIC CHANGES IN WHITE ADIPOSE TISSUE (WAT) AND THE LIVER AND GENERATE SECONDARY HYPOTHESES ON HOW EXERCISE MAY IMPACT METABOLISM-RELATED EPIGENETIC MARKS IN THESE TISSUES. MAJOR CONCLUSIONS: EPIGENETIC CHANGES CONTRIBUTE TO THE COMPLEX TRANSCRIPTIONAL RESPONSES ASSOCIATED WITH WAT LIPOLYSIS, HEPATIC DE NOVO LIPOGENESIS, AND HEPATIC GLUCONEOGENESIS. WHILE THESE METABOLIC RESPONSES MAY HYPOTHETICALLY BE ALTERED WITH ACUTE AND CHRONIC EXERCISE, DIRECT TESTING IS NEEDED. 2021 3 5878 27 SYNERGISTIC EFFECTS OF HYPERANDROGENEMIA AND OBESOGENIC WESTERN-STYLE DIET ON TRANSCRIPTION AND DNA METHYLATION IN VISCERAL ADIPOSE TISSUE OF NONHUMAN PRIMATES. POLYCYSTIC OVARY SYNDROME (PCOS) IS A MAJOR REPRODUCTIVE DISORDER THAT IS RESPONSIBLE FOR 80% OF ANOVULATORY INFERTILITY AND THAT IS ASSOCIATED WITH HYPERANDROGENEMIA, INCREASED RISK OF OBESITY, AND WHITE ADIPOSE TISSUE (WAT) DYSFUNCTION. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMBINATION OF CHRONIC TESTOSTERONE (T) TREATMENT AND AN OBESOGENIC WESTERN-STYLE DIET (WSD) EXERTS SYNERGISTIC FUNCTIONAL EFFECTS ON WAT, LEADING TO INCREASED LIPID ACCUMULATION IN VISCERAL ADIPOCYTES BY AN UNKNOWN MECHANISM. IN THIS STUDY, WE EXAMINED THE WHOLE-GENOME TRANSCRIPTIONAL RESPONSE IN VISCERAL WAT TO T AND WSD, ALONE AND IN COMBINATION. WE OBSERVED A SYNERGISTIC EFFECT OF T AND WSD ON GENE EXPRESSION, RESULTING IN UPREGULATION OF LIPID STORAGE GENES CONCOMITANT WITH ADIPOCYTE HYPERTROPHY. BECAUSE DNA METHYLATION IS KNOWN TO BE ASSOCIATED WITH BODY FAT DISTRIBUTION AND THE ETIOLOGY OF PCOS, WE CONDUCTED WHOLE-GENOME DNA METHYLATION ANALYSIS OF VISCERAL WAT. WHILE ONLY A FRACTION OF DIFFERENTIALLY EXPRESSED GENES ALSO EXHIBITED DIFFERENTIAL DNA METHYLATION, IN SILICO ANALYSIS SHOWED THAT DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN TRANSCRIPTION FACTOR BINDING MOTIFS, SUGGESTING A POTENTIAL GENE REGULATORY ROLE FOR THESE REGIONS. IN SUMMARY, THIS STUDY DEMONSTRATES THAT HYPERANDROGENEMIA ALONE DOES NOT INDUCE GLOBAL TRANSCRIPTIONAL AND EPIGENETIC RESPONSE IN YOUNG FEMALE MACAQUES UNLESS COMBINED WITH AN OBESOGENIC DIET. 2019 4 1900 26 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 5 3436 27 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 6 2336 26 EPIGENETIC REGULATION OF INFLAMMATORY FACTORS IN ADIPOSE TISSUE. OBESITY IS A STRONG RISK FACTOR FOR INSULIN RESISTANCE. CHRONIC LOW-GRADE TISSUE INFLAMMATION AND SYSTEMIC INFLAMMATION HAVE BEEN PROPOSED AS MAJOR MECHANISMS THAT PROMOTE INSULIN RESISTANCE IN OBESITY. ADIPOSE TISSUE HAS BEEN RECOGNIZED AS A NEXUS BETWEEN INFLAMMATION AND METABOLISM, BUT HOW EXACTLY INFLAMMATORY GENE EXPRESSION IS ORCHESTRATED DURING THE DEVELOPMENT OF OBESITY IS NOT WELL UNDERSTOOD. EPIGENETIC MODIFICATIONS ARE DEFINED AS HERITABLE CHANGES IN GENE EXPRESSION AND CELLULAR FUNCTION WITHOUT CHANGES TO THE ORIGINAL DNA SEQUENCE. THE MAJOR EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS, NUCLEOPOSITIONING/REMODELING AND CHROMATIN REORGANIZATION. EPIGENETIC MECHANISMS PROVIDE A CRITICAL LAYER OF GENE REGULATION IN RESPONSE TO ENVIRONMENTAL CHANGES. ACCUMULATING EVIDENCE SUPPORTS THAT EPIGENETICS PLAYS A LARGE ROLE IN THE REGULATION OF INFLAMMATORY GENES IN ADIPOCYTES AND ADIPOSE-RESIDENT IMMUNE CELL TYPES. THIS REVIEW FOCUSES ON THE ASSOCIATION BETWEEN ADIPOSE TISSUE INFLAMMATION IN OBESITY AND MAJOR EPIGENETIC MODIFICATIONS. 2021 7 2002 23 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 8 2332 26 EPIGENETIC REGULATION OF INFLAMMATION IN INSULIN RESISTANCE. EPIGENETICS FOCUSES ON THE STUDY OF CHANGES IN GENE EXPRESSION BASED ON MODIFICATIONS THAT DO NOT INTERFERE WITH THE DNA SEQUENCE, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATION, AND NON-CODING RNA. EPIGENETIC CHANGES REGULATE THE EXPRESSION OF MANY GENES, INCLUDING INFLAMMATORY ONES. CHRONIC INFLAMMATION IS OFTEN ACCOMPANIED BY INSULIN RESISTANCE (IR), WHICH IS CHARACTERISTIC OF INTER ALIA TYPE 2 DIABETES. RECENTLY, IT HAS BEEN REPORTED THAT ALTERED EPIGENETIC SIGNATURE IN THE PROMOTER REGIONS OF INFLAMMATORY GENES MAY CONTRIBUTE TO THE DEVELOPMENT OF IR. THEREFORE, THE AIM OF THIS REVIEW IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC REGULATION OF INFLAMMATION IN IR. IT INCLUDES ORIGINAL PAPERS PUBLISHED FROM 2014 TO 2022. IT APPEARS THAT HYPOMETHYLATION OF THE SOCS3 GENE INCREASES THE RISK OF IR, WHILE THE ALTERATION OF H3K4ME IN THE NF-KB PROMOTER PROMOTES CHANGES IN INFLAMMATORY PHENOTYPE. FINALLY, IN HYPERGLYCEMIC STATES ASSOCIATED WITH IR, ALTERED LEVELS OF H3K4/K9M3 AND H3K9/K14AC RESULT IN INCREASED EXPRESSION OF THE INFLAMMATORY CYTOKINE IL-6. IN ADDITION, NUMEROUS MIRNAS HAVE BEEN IDENTIFIED THAT MAY BECOME A TARGET IN THE FIGHT AGAINST DISEASES RELATED TO INFLAMMATION AND IR. FUTURE STUDIES SHOULD EXAMINE THE EPIGENETIC MODIFICATIONS OF IR INFLAMMATORY MARKERS ASSOCIATED WITH ENVIRONMENTAL FACTORS. 2022 9 4455 26 MOLECULAR MECHANISMS FOR THE VICIOUS CYCLE BETWEEN INSULIN RESISTANCE AND THE INFLAMMATORY RESPONSE IN OBESITY. THE COMPREHENSIVE ANABOLIC EFFECTS OF INSULIN THROUGHOUT THE BODY, IN ADDITION TO THE CONTROL OF GLYCEMIA, INCLUDE ENSURING LIPID HOMEOSTASIS AND ANTI-INFLAMMATORY MODULATION, ESPECIALLY IN ADIPOSE TISSUE (AT). THE PREVALENCE OF OBESITY, DEFINED AS A BODY MASS INDEX (BMI) >/= 30 KG/M(2), HAS BEEN INCREASING WORLDWIDE ON A PANDEMIC SCALE WITH ACCOMPANYING SYNDEMIC HEALTH PROBLEMS, INCLUDING GLUCOSE INTOLERANCE, INSULIN RESISTANCE (IR), AND DIABETES. IMPAIRED TISSUE SENSITIVITY TO INSULIN OR IR PARADOXICALLY LEADS TO DISEASES WITH AN INFLAMMATORY COMPONENT DESPITE HYPERINSULINEMIA. THEREFORE, AN EXCESS OF VISCERAL AT IN OBESITY INITIATES CHRONIC LOW-GRADE INFLAMMATORY CONDITIONS THAT INTERFERE WITH INSULIN SIGNALING VIA INSULIN RECEPTORS (INSRS). MOREOVER, IN RESPONSE TO IR, HYPERGLYCEMIA ITSELF STIMULATES A PRIMARILY DEFENSIVE INFLAMMATORY RESPONSE ASSOCIATED WITH THE SUBSEQUENT RELEASE OF NUMEROUS INFLAMMATORY CYTOKINES AND A REAL THREAT OF ORGAN FUNCTION DETERIORATION. IN THIS REVIEW, ALL COMPONENTS OF THIS VICIOUS CYCLE ARE CHARACTERIZED WITH PARTICULAR EMPHASIS ON THE INTERPLAY BETWEEN INSULIN SIGNALING AND BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES RELATED TO OBESITY. INCREASED VISCERAL AT ACCUMULATION IN OBESITY SHOULD BE CONSIDERED THE MAIN ENVIRONMENTAL FACTOR RESPONSIBLE FOR THE DISRUPTION IN THE EPIGENETIC REGULATORY MECHANISMS IN THE IMMUNE SYSTEM, RESULTING IN AUTOIMMUNITY AND INFLAMMATION. 2023 10 37 32 A CHROMATIN REMODELING CHECKPOINT OF DIET-INDUCED MACROPHAGE ACTIVATION IN ADIPOSE TISSUE. THE INTERPLAY BETWEEN THE ENVIRONMENT AND THE IMMUNE CELLS IS LINKED TO METABOLIC HOMEOSTASIS UNDER PHYSIOLOGIC AND PATHOPHYSIOLOGIC CONDITIONS. DIABETES MELLITUS TYPE 2 (T2D) IS CONSIDERED AN IMMUNE-RELATED INFLAMMATORY DISORDER, IN WHICH THE ADIPOSE TISSUE MACROPHAGES (ATMS) ARE KEY PLAYERS ORCHESTRATING METABOLIC CHRONIC META-INFLAMMATION AND CONTRIBUTING TO THE PATHOGENESIS OF METABOLIC DISEASE. HOWEVER, THE MOLECULAR REGULATORS THAT INTEGRATE THE ENVIRONMENTAL SIGNALS TO CONTROL ATM ACTIVATION AND ADIPOSE INFLAMMATION DURING OBESITY AND T2D REMAIN UNCLEAR. EPIGENETIC MECHANISMS CONSTITUTE IMPORTANT PARAMETERS IN METABOLIC HOMEOSTASIS, OBESITY AND T2D VIA THE INTEGRATION OF THE ENVIRONMENTAL FACTORS TO THE TRANSCRIPTIONAL REGULATION OF GENE PROGRAMS. IN A VERY RECENT STUDY PUBLISHED IN DIABETES BY KONG ET AL., BAF60A HAS BEEN IDENTIFIED AS A KEY CHROMATIN REMODELING CHECKPOINT FACTOR THAT ASSOCIATES OBESITY-ASSOCIATED STRESS SIGNALS WITH META-INFLAMMATION AND SYSTEMIC HOMEOSTASIS. FURTHERMORE, THIS WORK UNCOVERS ATF3 AS AN IMPORTANT DOWNSTREAM EFFECTOR IN BAF60A-MEDIATED CHROMATIN REMODELING AND TRANSCRIPTIONAL REPROGRAMMING OF MACROPHAGE ACTIVATION IN ADIPOSE TISSUE. THE FINDINGS OF THIS RESEARCH MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW THERAPEUTIC APPROACHES FOR OBESITY-INDUCED METABOLIC INFLAMMATION AND ASSOCIATED METABOLIC DISORDERS. 2022 11 2964 20 GENETIC AND EPIGENETIC MECHANISMS UNDERLYING ARSENIC-ASSOCIATED DIABETES MELLITUS: A PERSPECTIVE OF THE CURRENT EVIDENCE. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF DIABETES MELLITUS (DM), A DISEASE CHARACTERIZED BY HYPERGLYCEMIA RESULTING FROM DYSREGULATION OF GLUCOSE HOMEOSTASIS. THIS REVIEW SUMMARIZES FOUR MAJOR MECHANISMS BY WHICH ARSENIC INDUCES DIABETES, NAMELY INHIBITION OF INSULIN-DEPENDENT GLUCOSE UPTAKE, PANCREATIC BETA-CELL DAMAGE, PANCREATIC BETA-CELL DYSFUNCTION AND STIMULATION OF LIVER GLUCONEOGENESIS THAT ARE SUPPORTED BY BOTH IN VIVO AND IN VITRO STUDIES. ADDITIONALLY, THE ROLE OF POLYMORPHIC VARIANTS ASSOCIATED WITH ARSENIC TOXICITY AND DISEASE SUSCEPTIBILITY, AS WELL AS EPIGENETIC MODIFICATIONS ASSOCIATED WITH ARSENIC EXPOSURE, ARE CONSIDERED IN THE CONTEXT OF ARSENIC-ASSOCIATED DM. TAKEN TOGETHER, IN VITRO, IN VIVO AND HUMAN GENETIC/EPIGENETIC STUDIES SUPPORT THAT ARSENIC HAS THE POTENTIAL TO INDUCE DM PHENOTYPES AND IMPAIR KEY PATHWAYS INVOLVED IN THE REGULATION OF GLUCOSE HOMEOSTASIS. 2017 12 4022 24 LSD1 FOR THE TARGETED REGULATION OF ADIPOSE TISSUE. WHITE AND THERMAL (BROWN AND BEIGE) ADIPOSE TISSUE ENERGY STORAGE AND OXIDATIVE REGULATION PATHWAYS PLAY A CENTRAL ROLE IN MAINTAINING THE ENERGY BALANCE THROUGHOUT THE BODY, AND THE DYSREGULATION OF THESE PATHWAYS IS CLOSELY RELATED TO GLUCOSE AND LIPID METABOLISM DISORDERS AND ADIPOSE TISSUE DYSFUNCTION, INCLUDING OBESITY, CHRONIC INFLAMMATION, INSULIN RESISTANCE, MITOCHONDRIAL DYSFUNCTION, AND FIBROSIS. RECENT EPIGENETIC STUDIES HAVE IDENTIFIED THE NOVEL REGULATORY ELEMENT LSD1, WHICH CONTROLS THE ABOVE PARAMETERS, AND HAVE PROVIDED NEW MECHANISTIC POSSIBILITIES FOR RE-ENCODING THE FATE AND FUNCTION OF ADIPOCYTES. IN THIS REVIEW, WE OUTLINE THE CURRENT ADVANCES IN ADIPOCYTE METABOLISM IN PHYSIOLOGY AND DISEASE AND DISCUSS POSSIBLE STRATEGIES FOR LSD1 TO ALTER THE PHENOTYPE OF ADIPOSE TISSUE AND THUS INFLUENCE ENERGY UTILIZATION TO IMPROVE METABOLIC HEALTH. 2022 13 6200 25 THE INFLAMMATORY EFFECT OF EPIGENETIC FACTORS AND MODIFICATIONS IN TYPE 2 DIABETES. INFLAMMATION HAS A CENTRAL ROLE IN THE ETIOLOGY OF TYPE 2 DIABETES (T2D) AND ITS COMPLICATIONS. BOTH GENETIC AND EPIGENETIC FACTORS HAVE BEEN IMPLICATED IN THE DEVELOPMENT OF T2D-ASSOCIATED INFLAMMATION. EPIGENETIC MECHANISMS REGULATE THE FUNCTION OF SEVERAL COMPONENTS OF THE IMMUNE SYSTEM. DIABETIC CONDITIONS TRIGGER ABERRANT EPIGENETIC ALTERATIONS THAT CONTRIBUTE TO THE PROGRESSION OF INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION BY INDUCTION OF INFLAMMATORY RESPONSES. THUS, TARGETING EPIGENETIC FACTORS AND MODIFICATIONS, AS ONE OF THE UNDERLYING CAUSES OF INFLAMMATION, COULD LEAD TO THE DEVELOPMENT OF NOVEL IMMUNE-BASED STRATEGIES FOR THE TREATMENT OF T2D. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE EPIGENETIC MECHANISMS INVOLVED IN THE PROPAGATION AND PERPETUATION OF CHRONIC INFLAMMATION IN T2D. WE ALSO DISCUSS THE POSSIBLE ANTI-INFLAMMATORY APPROACHES THAT TARGET EPIGENETIC FACTORS FOR THE TREATMENT OF T2D. 2020 14 4391 29 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 15 6022 26 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 16 776 27 CELL- AND TISSUE-SPECIFIC EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC INFLAMMATION IN INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) IS A CHRONIC METABOLIC DISORDER CHARACTERIZED BY HYPERGLYCAEMIA, WHICH CAN CAUSE MICRO- AND MACROVASCULAR COMPLICATIONS. CHRONIC INFLAMMATION MAY BE THE CAUSE AND RESULT OF T2DM, AND ITS RELATED COMPLICATIONS AS AN IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY CYTOKINES CAN AFFECT IMMUNE FUNCTIONS. APART FROM GENETIC CHANGES OCCURRING WITHIN THE BODY RESULTING IN INFLAMMATION IN T2DM, EPIGENETIC MODIFICATIONS CAN MODIFY GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES SUCH AS AN UNHEALTHY DIET, LACK OF EXERCISE AND OBESITY. THE MOST WIDELY STUDIED EPIGENETIC MODIFICATION, DNA METHYLATION (DNAM), REGULATES GENE EXPRESSION AND MAY MANIPULATE INFLAMMATORY GENES TO INCREASE OR DECREASE INFLAMMATION ASSOCIATED WITH T2DM. THIS REVIEW EXPLORES THE STUDIES RELATED TO EPIGENETIC CHANGES, MORE SPECIFICALLY DNAM, ASSOCIATED WITH CHRONIC INFLAMMATION IN T2DM, AT BOTH THE CELL AND TISSUE LEVELS. STUDYING EPIGENETIC ALTERATIONS DURING INFLAMMATORY RESPONSE, AS A RESULT OF GENETIC AND ENVIRONMENTAL SIGNALS, CREATES OPPORTUNITIES FOR THE DEVELOPMENT OF "EARLY DETECTION/RELATIVE RISK" TESTS TO AID IN PREVENTION OF T2DM. UNDERSTANDING INFLAMMATION IN T2DM AT THE GENE LEVEL IN INFLAMMATION-ASSOCIATED CELLS AND TISSUES MAY PROVIDE FURTHER INSIGHT FOR THE DEVELOPMENT OF SPECIFIC THERAPEUTIC TARGETS FOR THE DISORDER. 2018 17 44 31 A COMPREHENSIVE REVIEW ON HIGH -FAT DIET-INDUCED DIABETES MELLITUS: AN EPIGENETIC VIEW. MODERN LIFESTYLE, GENETICS, NUTRITIONAL OVERLOAD THROUGH HIGH-FAT DIET ATTRIBUTED PREVALENCE AND DIABETES OUTCOMES WITH VARIOUS COMPLICATIONS PRIMARILY DUE TO OBESITY IN WHICH ENERGY-DENSE DIETS FREQUENTLY AFFECT METABOLIC HEALTH. ONE POSSIBLE ISSUE USUALLY ASSOCIATED WITH ELEVATED CHRONIC FAT INTAKE IS INSULIN RESISTANCE, AND HYPERGLYCEMIA CONSTITUTES AN IMPORTANT FUNCTION IN ALTERING THE CARBOHYDRATES AND LIPIDS METABOLISM. SIMILARLY, IN ASSESSING HUMAN SUSCEPTIBILITY TO WEIGHT GAIN AND OBESITY, GENETIC VARIATIONS PLAY A CENTRAL ROLE, CONTRIBUTING TO KEEN INTEREST IN IDENTIFYING THE POSSIBLE ROLE OF EPIGENETICS AS A MEDIATOR OF GENE-ENVIRONMENTAL INTERACTIONS INFLUENCING THE PRODUCTION OF TYPE 2 DIABETES MELLITUS AND ITS RELATED CONCERNS. EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE ACCEPTANCE OF A SEDENTARY LIFESTYLE AND ENVIRONMENTAL STRESS FACTORS IN RESPONSE TO ENERGY INTAKE AND EXPENDITURE IMBALANCES COMPLEMENT GENETIC ALTERATIONS AND LEAD TO THE PRODUCTION AND ADVANCEMENT OF METABOLIC DISORDERS SUCH AS DIABETES AND OBESITY. METHYLATION OF DNA, HISTONE MODIFICATIONS, AND INCREASES IN THE EXPRESSION OF NON-CODING RNAS CAN RESULT IN REDUCED TRANSCRIPTIONAL ACTIVITY OF KEY BETA-CELL GENES THUS CREATING INSULIN RESISTANCE. EPIGENETICS CONTRIBUTE TO CHANGES IN THE EXPRESSION OF THE UNDERLYING INSULIN RESISTANCE AND INSUFFICIENCY GENE NETWORKS, ALONG WITH LOW-GRADE OBESITY-RELATED INFLAMMATION, INCREASED ROS GENERATION, AND DNA DAMAGE IN MULTIORGANS. THIS REVIEW FOCUSED ON EPIGENETIC MECHANISMS AND METABOLIC REGULATIONS ASSOCIATED WITH HIGH-FAT DIET (HFD)-INDUCED DIABETES MELLITUS. 2022 18 4801 22 OBESITY AND INSULIN RESISTANCE: ASSOCIATIONS WITH CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS. BACKGROUND: OBESITY IS KNOWN TO BE A MULTIFACTORIAL DISEASE. IN ITS PATHOGENESIS, DIFFERENT FACTORS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, INSULIN RESISTANCE, GENETIC FACTORS, ENVIRONMENTAL EFFECTS, VEGETATIVE DISTURBANCE, AND UNBALANCED NUTRITION PLAY A SIGNIFICANT ROLE. METHODOLOGY: THIS STUDY DESCRIBES THE ASSOCIATION OF OBESITY AND INSULIN RESISTANCE WITH CHRONIC INFLAMMATION, GENETIC, AND EPIGENETIC FACTORS. PREVIOUS LITERATURE HAS BEEN REVIEWED TO EXPLAIN THE RELATION OF OBESITY WITH THOSE FACTORS INVOLVED IN CHRONIC LOW-GRADE INFLAMMATION AND INSULIN. RESULTS: OBESITY IS ASSOCIATED WITH A DECREASE IN GHRELIN SECRETION, ELEVATED PLASMA LEPTIN LEVELS, OXIDATIVE STRESS, INCREASED MACROPHAGE PHAGOCYTIC ACTIVITY, AND THE INDUCTION OF PROINFLAMMATORY SYNTHESIS OF CYTOKINES AND INTERFERON-GAMMA. OBESITY IS LINKED TO DECREASED LEVELS OF CYTOCHROME P450 (CYP) ENZYMES AND IMPAIRED DETOXIFICATION PROCESSES. DEFICIENCY OF VITAMINS AND MINERALS CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF OXIDATIVE STRESS AND CHRONIC INFLAMMATION IN OBESITY. THERE IS EVIDENCE OF ASSOCIATIONS BETWEEN A GENETIC PREDISPOSITION TO OBESITY IN CHILDREN WITH ELEVATED LEVELS OF CERTAIN MIRNAS. CONCLUSION: THE PURPOSE OF THE PRESENT REVIEW IS AN ANALYSIS OF THE MULTIPLE FACTORS ASSOCIATED WITH OBESITY. 2021 19 1017 20 CIRCADIAN RHYTHMS IN LIVER PHYSIOLOGY AND LIVER DISEASES. IN MAMMALS, CIRCADIAN RHYTHMS FUNCTION TO COORDINATE A DIVERSE PANEL OF PHYSIOLOGICAL PROCESSES WITH ENVIRONMENTAL CONDITIONS SUCH AS FOOD AND LIGHT. AS THE DRIVING FORCE FOR CIRCADIAN RHYTHMICITY, THE MOLECULAR CLOCK IS A SELF-SUSTAINED TRANSCRIPTION-TRANSLATIONAL FEEDBACK LOOP SYSTEM CONSISTING OF TRANSCRIPTION FACTORS, EPIGENETIC MODULATORS, KINASES/PHOSPHATASES, AND UBIQUITIN E3 LIGASES. THE MOLECULAR CLOCK EXISTS NOT ONLY IN THE SUPRACHIASMATIC NUCLEI OF THE HYPOTHALAMUS BUT ALSO IN THE PERIPHERAL TISSUES TO REGULATE CELLULAR AND PHYSIOLOGICAL FUNCTION IN A TISSUE-SPECIFIC MANNER. THE CIRCADIAN CLOCK SYSTEM IN THE LIVER PLAYS IMPORTANT ROLES IN REGULATING METABOLISM AND ENERGY HOMEOSTASIS. CLOCK GENE MUTANT ANIMALS DISPLAY IMPAIRED GLUCOSE AND LIPID METABOLISM AND ARE SUSCEPTIBLE TO DIET-INDUCED OBESITY AND METABOLIC DYSFUNCTION, PROVIDING STRONG EVIDENCE FOR THE CONNECTION BETWEEN THE CIRCADIAN CLOCK AND METABOLIC HOMEOSTASIS. CIRCADIAN-CONTROLLED HEPATIC METABOLISM IS PARTIALLY ACHIEVED BY CONTROLLING THE EXPRESSION AND/OR ACTIVITY OF KEY METABOLIC ENZYMES, TRANSCRIPTION FACTORS, SIGNALING MOLECULES, AND TRANSPORTERS. RECIPROCALLY, INTRACELLULAR METABOLITES MODULATE THE MOLECULAR CLOCK ACTIVITY IN RESPONSE TO THE ENERGY STATUS. ALTHOUGH STILL AT THE EARLY STAGE, CIRCADIAN CLOCK DYSFUNCTION HAS BEEN IMPLICATED IN COMMON CHRONIC LIVER DISEASES. CIRCADIAN DYSREGULATION OF LIPID METABOLISM, DETOXIFICATION, REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, AND CELL-CYCLE CONTROL MIGHT CONTRIBUTE TO THE ONSET AND PROGRESSION OF LIVER STEATOSIS, FIBROSIS, AND EVEN CARCINOGENESIS. IN SUMMARY, THESE FINDINGS CALL FOR A COMPREHENSIVE STUDY OF THE FUNCTION AND MECHANISMS OF HEPATIC CIRCADIAN CLOCK TO GAIN BETTER UNDERSTANDING OF LIVER PHYSIOLOGY AND DISEASES. 2013 20 4185 23 METABOLIC ADAPTIONS/REPROGRAMMING IN ISLET BETA-CELLS IN RESPONSE TO PHYSIOLOGICAL STIMULATORS-WHAT ARE THE CONSEQUENCES. IRREVERSIBLE PANCREATIC BETA-CELL DAMAGE MAY BE A RESULT OF CHRONIC EXPOSURE TO SUPRAPHYSIOLOGICAL GLUCOSE OR LIPID CONCENTRATIONS OR CHRONIC EXPOSURE TO THERAPEUTIC ANTI-DIABETIC DRUGS. THE BETA-CELLS ARE ABLE TO RESPOND TO BLOOD GLUCOSE IN A NARROW CONCENTRATION RANGE AND RELEASE INSULIN IN RESPONSE, FOLLOWING ACTIVATION OF METABOLIC PATHWAYS SUCH AS GLYCOLYSIS AND THE TCA CYCLE. THE BETA-CELL CANNOT PROTECT ITSELF FROM GLUCOSE TOXICITY BY BLOCKING GLUCOSE UPTAKE, BUT INDEED RELIES ON ALTERNATIVE METABOLIC PROTECTION MECHANISMS TO AVOID DYSFUNCTION AND DEATH. ALTERATION OF NORMAL METABOLIC PATHWAY FUNCTION OCCURS AS A COUNTER REGULATORY RESPONSE TO HIGH NUTRIENT, INFLAMMATORY FACTOR, HORMONE OR THERAPEUTIC DRUG CONCENTRATIONS. METABOLIC REPROGRAMMING IS A TERM WIDELY USED TO DESCRIBE A CHANGE IN REGULATION OF VARIOUS METABOLIC ENZYMES AND TRANSPORTERS, USUALLY ASSOCIATED WITH CELL GROWTH AND PROLIFERATION AND MAY INVOLVE RESHAPING EPIGENETIC RESPONSES, IN PARTICULAR THE ACETYLATION AND METHYLATION OF HISTONE PROTEINS AND DNA. OTHER METABOLIC MODIFICATIONS SUCH AS MALONYLATION, SUCCINYLATION, HYDROXYBUTYRYLATION, ADP-RIBOSYLATION, AND LACTYLATION, MAY IMPACT REGULATORY PROCESSES, MANY OF WHICH NEED TO BE INVESTIGATED IN DETAIL TO CONTRIBUTE TO CURRENT ADVANCES IN METABOLISM. BY DESCRIBING MULTIPLE MECHANISMS OF METABOLIC ADAPTION THAT ARE AVAILABLE TO THE BETA-CELL ACROSS ITS LIFESPAN, WE HOPE TO IDENTIFY SITES FOR METABOLIC REPROGRAMMING MECHANISMS, MOST OF WHICH ARE INCOMPLETELY DESCRIBED OR UNDERSTOOD. MANY OF THESE MECHANISMS ARE RELATED TO PROMINENT ANTIOXIDANT RESPONSES. HERE, WE HAVE ATTEMPTED TO DESCRIBE THE KEY BETA-CELL METABOLIC ADAPTIONS AND CHANGES WHICH ARE REQUIRED FOR SURVIVAL AND FUNCTION IN VARIOUS PHYSIOLOGICAL, PATHOLOGICAL AND PHARMACOLOGICAL CONDITIONS. 2022