1 3359 128 HISTONE H4 LYSINE 16 ACETYLATION CONTROLS CENTRAL CARBON METABOLISM AND DIET-INDUCED OBESITY IN MICE. NONCOMMUNICABLE DISEASES (NCDS) ACCOUNT FOR OVER 70% OF DEATHS WORLD-WIDE. PREVIOUS WORK HAS LINKED NCDS SUCH AS TYPE 2 DIABETES (T2D) TO DISRUPTION OF CHROMATIN REGULATORS. HOWEVER, THE EXACT MOLECULAR ORIGINS OF THESE CHRONIC CONDITIONS REMAIN ELUSIVE. HERE, WE IDENTIFY THE H4 LYSINE 16 ACETYLTRANSFERASE MOF AS A CRITICAL REGULATOR OF CENTRAL CARBON METABOLISM. HIGH-THROUGHPUT METABOLOMICS UNVEIL A SYSTEMIC AMINO ACID AND CARBOHYDRATE IMBALANCE IN MOF DEFICIENT MICE, MANIFESTING IN T2D PREDISPOSITION. ORAL GLUCOSE TOLERANCE TESTING (OGTT) REVEALS DEFECTS IN GLUCOSE ASSIMILATION AND INSULIN SECRETION IN THESE ANIMALS. FURTHERMORE, MOF DEFICIENT MICE ARE RESISTANT TO DIET-INDUCED FAT GAIN DUE TO DEFECTS IN GLUCOSE UPTAKE IN ADIPOSE TISSUE. MOF-MEDIATED H4K16AC DEPOSITION CONTROLS EXPRESSION OF THE MASTER REGULATOR OF GLUCOSE METABOLISM, PPARG AND THE ENTIRE DOWNSTREAM TRANSCRIPTIONAL NETWORK. GLUCOSE UPTAKE AND LIPID STORAGE CAN BE RECONSTITUTED IN MOF-DEPLETED ADIPOCYTES IN VITRO BY ECTOPIC GLUT4 EXPRESSION, PPARGAMMA AGONIST THIAZOLIDINEDIONE (TZD) TREATMENT OR SIRT1 INHIBITION. HENCE, CHRONIC IMBALANCE IN H4K16AC PROMOTES A DESTABILISATION OF METABOLISM TRIGGERING THE DEVELOPMENT OF A METABOLIC DISORDER, AND ITS MAINTENANCE PROVIDES AN UNPRECEDENTED REGULATORY EPIGENETIC MECHANISM CONTROLLING DIET-INDUCED OBESITY. 2021 2 1900 32 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 3 5438 22 REMOVAL OF EPIGENETIC REPRESSIVE MARK ON INFLAMMATORY GENES IN FAT LIVER. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE. THE DETAILED EPIGENOMIC CHANGES DURING FAT ACCUMULATION IN LIVER ARE NOT CLEAR YET. HERE, WE PERFORMED CHIP-SEQ ANALYSIS IN THE LIVER TISSUES OF HIGH-FAT DIET AND REGULAR CHOW DIET MICE AND INVESTIGATED THE DYNAMIC LANDSCAPES OF H3K27AC AND H3K9ME3 MARKS ON CHROMATIN. WE FIND THAT THE ACTIVATED TYPICAL ENHANCERS MARKED WITH H3K27AC ARE ENRICHED ON LIPID METABOLIC PATHWAYS IN FAT LIVER; HOWEVER, SUPER ENHANCERS DO NOT CHANGE MUCH. THE REGIONS COVERED WITH H3K9ME3 REPRESSIVE MARK SEEM TO UNDERGO GREAT CHANGES, AND ITS PEAK NUMBER AND INTENSITY BOTH DECREASE IN FAT LIVER. THE ENHANCERS LOCATED IN LOST H3K9ME3 REGIONS ARE ENRICHED IN LIPID METABOLISM AND INFLAMMATORY PATHWAYS; AND MOTIF ANALYSIS SHOWS THAT THEY ARE POTENTIAL TARGETS FOR TRANSCRIPTION FACTORS INVOLVED IN METABOLIC AND INFLAMMATORY PROCESSES. OUR STUDY HAS REVEALED THAT H3K9ME3 MAY PLAY AN IMPORTANT ROLE DURING THE PATHOGENESIS OF NAFLD THROUGH REGULATING THE ACCESSIBILITY OF ENHANCERS. 2023 4 2549 33 EPIGENETICS IN OBESITY AND DIABETES MELLITUS: NEW INSIGHTS. A LONG-TERM COMPLICATION OF OBESITY IS THE DEVELOPMENT OF TYPE 2 DIABETES (T2D). PATIENTS WITH T2D HAVE BEEN DESCRIBED AS HAVING EPIGENETIC MODIFICATIONS. EPIGENETICS IS THE POST-TRANSCRIPTIONAL MODIFICATION OF DNA OR ASSOCIATED FACTORS CONTAINING GENETIC INFORMATION. THESE ENVIRONMENTALLY-INFLUENCED MODIFICATIONS, MAINTAINED DURING CELL DIVISION, CAUSE STABLE CHANGES IN GENE EXPRESSION. EPIGENETIC MODIFICATIONS OF T2D ARE DNA METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION AT THE LYSINE RESIDUE AT THE AMINO TERMINUS OF HISTONES, AFFECTING DNA, HISTONES, AND NON-CODING RNA. DNA METHYLATION HAS BEEN SHOWN IN PANCREATIC ISLETS, ADIPOSE TISSUE, SKELETAL MUSCLE, AND THE LIVER. FURTHERMORE, EPIGENETIC CHANGES HAVE BEEN OBSERVED IN CHRONIC COMPLICATIONS OF T2D, SUCH AS DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY, AND DIABETIC NEUROPATHY. RECENTLY, A NEW DRUG HAS BEEN DEVELOPED WHICH ACTS ON BROMODOMAINS AND EXTRATERMINAL (BET) DOMAIN PROTEINS, WHICH OPERATE LIKE EPIGENETIC READERS AND COMMUNICATE WITH CHROMATIN TO MAKE DNA ACCESSIBLE FOR TRANSCRIPTION BY INHIBITING THEM. THIS DRUG (APABETALONE) IS BEING STUDIED TO PREVENT MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PEOPLE WITH T2D, LOW HDL CHOLESTEROL, CHRONIC KIDNEY FAILURE, AND RECENT CORONARY EVENTS. THIS REVIEW AIMS TO DESCRIBE THE RELATIONSHIP BETWEEN OBESITY, LONG-TERM COMPLICATIONS SUCH AS T2D, AND EPIGENETIC MODIFICATIONS AND THEIR POSSIBLE TREATMENTS. 2023 5 44 32 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 6 3292 37 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS. 2017 7 420 29 ANDROGEN-MEDIATED PERTURBATION OF THE HEPATIC CIRCADIAN SYSTEM THROUGH EPIGENETIC MODULATION PROMOTES NAFLD IN PCOS MICE. IN WOMEN, EXCESS ANDROGEN CAUSES POLYCYSTIC OVARY SYNDROME (PCOS), A COMMON FERTILITY DISORDER WITH COMORBID METABOLIC DYSFUNCTIONS INCLUDING DIABETES, OBESITY, AND NONALCOHOLIC FATTY LIVER DISEASE. USING A PCOS MOUSE MODEL, THIS STUDY SHOWS THAT CHRONIC HIGH ANDROGEN LEVELS CAUSE HEPATIC STEATOSIS WHILE HEPATOCYTE-SPECIFIC ANDROGEN RECEPTOR (AR)-KNOCKOUT RESCUES THIS PHENOTYPE. MOREOVER, THROUGH RNA-SEQUENCING AND METABOLOMIC STUDIES, WE HAVE IDENTIFIED KEY METABOLIC GENES AND PATHWAYS AFFECTED BY HYPERANDROGENISM. OUR STUDIES REVEAL THAT A LARGE NUMBER OF METABOLIC GENES ARE DIRECTLY REGULATED BY ANDROGENS THROUGH AR BINDING TO ANDROGEN RESPONSE ELEMENT SEQUENCES ON THE PROMOTER REGION OF THESE GENES. INTERESTINGLY, A NUMBER OF CIRCADIAN GENES ARE ALSO DIFFERENTIALLY REGULATED BY ANDROGENS. IN VIVO AND IN VITRO STUDIES USING A CIRCADIAN REPORTER [PERIOD2::LUCIFERASE (PER2::LUC)] MOUSE MODEL DEMONSTRATE THAT ANDROGENS CAN DIRECTLY DISRUPT THE HEPATIC TIMING SYSTEM, WHICH IS A KEY REGULATOR OF LIVER METABOLISM. CONSEQUENTLY, STUDIES SHOW THAT ANDROGENS DECREASE H3K27ME3, A GENE SILENCING MARK ON THE PROMOTER OF CORE CLOCK GENES, BY INHIBITING THE EXPRESSION OF HISTONE METHYLTRANSFERASE, EZH2, WHILE INDUCING THE EXPRESSION OF THE HISTONE DEMETHYLASE, JMJD3, WHICH IS RESPONSIBLE FOR ADDING AND REMOVING THE H3K27ME3 MARK, RESPECTIVELY. FINALLY, WE REPORT THAT UNDER HYPERANDROGENIC CONDITIONS, SOME OF THE SAME CIRCADIAN/METABOLIC GENES THAT ARE UPREGULATED IN THE MOUSE LIVER ARE ALSO ELEVATED IN NONHUMAN PRIMATE LIVERS. IN SUMMARY, THESE STUDIES NOT ONLY PROVIDE AN OVERALL UNDERSTANDING OF HOW HYPERANDROGENISM ASSOCIATED WITH PCOS AFFECTS LIVER GENE EXPRESSION AND METABOLISM BUT ALSO OFFER INSIGHT INTO THE UNDERLYING MECHANISMS LEADING TO HEPATIC STEATOSIS IN PCOS. 2022 8 4788 33 NUTRITION, EPIGENETICS, AND METABOLIC SYNDROME. SIGNIFICANCE: EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE DEMONSTRATED A CLOSE LINK BETWEEN MATERNAL NUTRITION AND CHRONIC METABOLIC DISEASE IN CHILDREN AND ADULTS. COMPELLING EXPERIMENTAL RESULTS ALSO INDICATE THAT ADVERSE EFFECTS OF INTRAUTERINE GROWTH RESTRICTION ON OFFSPRING CAN BE CARRIED FORWARD TO SUBSEQUENT GENERATIONS THROUGH COVALENT MODIFICATIONS OF DNA AND CORE HISTONES. RECENT ADVANCES: DNA METHYLATION IS CATALYZED BY S-ADENOSYLMETHIONINE-DEPENDENT DNA METHYLTRANSFERASES. METHYLATION, DEMETHYLATION, ACETYLATION, AND DEACETYLATION OF HISTONE PROTEINS ARE PERFORMED BY HISTONE METHYLTRANSFERASE, HISTONE DEMETHYLASE, HISTONE ACETYLTRANSFERASE, AND HISTONE DEACETYLTRANSFERASE, RESPECTIVELY. HISTONE ACTIVITIES ARE ALSO INFLUENCED BY PHOSPHORYLATION, UBIQUITINATION, ADP-RIBOSYLATION, SUMOYLATION, AND GLYCOSYLATION. METABOLISM OF AMINO ACIDS (GLYCINE, HISTIDINE, METHIONINE, AND SERINE) AND VITAMINS (B6, B12, AND FOLATE) PLAYS A KEY ROLE IN PROVISION OF METHYL DONORS FOR DNA AND PROTEIN METHYLATION. CRITICAL ISSUES: DISRUPTION OF EPIGENETIC MECHANISMS CAN RESULT IN OXIDATIVE STRESS, OBESITY, INSULIN RESISTANCE, DIABETES, AND VASCULAR DYSFUNCTION IN ANIMALS AND HUMANS. DESPITE A RECOGNIZED ROLE FOR EPIGENETICS IN FETAL PROGRAMMING OF METABOLIC SYNDROME, RESEARCH ON THERAPIES IS STILL IN ITS INFANCY. POSSIBLE INTERVENTIONS INCLUDE: 1) INHIBITION OF DNA METHYLATION, HISTONE DEACETYLATION, AND MICRORNA EXPRESSION; 2) TARGETING EPIGENETICALLY DISTURBED METABOLIC PATHWAYS; AND 3) DIETARY SUPPLEMENTATION WITH FUNCTIONAL AMINO ACIDS, VITAMINS, AND PHYTOCHEMICALS. FUTURE DIRECTIONS: MUCH WORK IS NEEDED WITH ANIMAL MODELS TO UNDERSTAND THE BASIC MECHANISMS RESPONSIBLE FOR THE ROLES OF SPECIFIC NUTRIENTS IN FETAL AND NEONATAL PROGRAMMING. SUCH NEW KNOWLEDGE IS CRUCIAL TO DESIGN EFFECTIVE THERAPEUTIC STRATEGIES FOR PREVENTING AND TREATING METABOLIC ABNORMALITIES IN OFFSPRING BORN TO MOTHERS WITH A PREVIOUS EXPERIENCE OF MALNUTRITION. 2012 9 215 36 ACUTE AND LONG-TERM NUTRIENT-LED MODIFICATIONS OF GENE EXPRESSION: POTENTIAL ROLE OF SIRT1 AS A CENTRAL CO-ORDINATOR OF SHORT AND LONGER-TERM PROGRAMMING OF TISSUE FUNCTION. ENVIRONMENTAL FACTORS CAN INFLUENCE THE ACUTE AND LONGER-TERM RISKS OF DEVELOPING DISEASES, INCLUDING TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE; HOWEVER, THE UNDERLYING MECHANISM REMAINS ELUSIVE. INCREASING EVIDENCE SUGGESTS THAT THESE EFFECTS CAN BE ACHIEVED BY MODIFICATION OF METABOLIC GENE EXPRESSION. THESE INCLUDE ACUTE CHANGES IN HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, AND UBIQUITINATION AND LONGER-TERM DNA SILENCING ELICITED BY DNA METHYLATION. THUS, AN INCREASED RISK OF DISEASE MAY REFLECT ACUTE OR CHRONIC STABLE MODIFICATION OF GENES THAT REGULATE NUTRIENT HANDLING, LEADING TO ALTERED NUTRIENT UTILIZATION (INCREASED LIPID OXIDATION AT THE EXPENSE OF GLUCOSE UTILIZATION) AND/OR CHANGES IN THE BALANCE BETWEEN NUTRIENT STORAGE AND ENERGY PRODUCTION, THEREBY FAVORING THE DEVELOPMENT OF OBESITY. THE REVIEW ADDRESSES THE HYPOTHESIS THAT EARLY-LIFE EPIGENETIC PROGRAMMING OF GENE EXPRESSION COULD BE MIRRORED BY CHANGES IN ACUTE FUNCTION OF NUCLEAR RECEPTORS, IN PARTICULAR THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS, ACHIEVED BY ENZYMES THAT ARE MORE CONVENTIONALLY INVOLVED IN REGULATING DNA METHYLATION AND POST-TRANSCRIPTIONAL MODIFICATION OF HISTONES. EMPHASIS IS PLACED ON THE POTENTIAL IMPORTANCE OF THE PROTEIN DEACETYLASE SIRTUIN-1 AS A CENTRAL CO-ORDINATOR. 2010 10 3836 31 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE. 2016 11 5074 23 PHYSIOLOGIC AND EPIGENETIC EFFECTS OF NUTRIENTS ON DISEASE PATHWAYS. BACKGROUND/OBJECTIVES: EPIGENETIC REGULATION BY NUTRIENTS CAN INFLUENCE THE DEVELOPMENT OF SPECIFIC DISEASES. THIS STUDY SOUGHT TO EXAMINE THE EFFECT OF INDIVIDUAL NUTRIENTS AND NUTRIENT FAMILIES IN THE CONTEXT OF PREVENTING CHRONIC METABOLIC DISEASES VIA EPIGENETIC REGULATION. THE INHIBITION OF LIPID ACCUMULATION AND INFLAMMATION BY NUTRIENTS INCLUDING PROTEINS, LIPIDS, VITAMINS, AND MINERALS WERE OBSERVED, AND HISTONE ACETYLATION BY HISTONE ACETYLTRANSFERASE (HAT) WAS MEASURED. CORRELATIVE ANALYSES WERE ALSO PERFORMED. MATERIALS/METHODS: NUTRIENTS WERE SELECTED ACCORDING TO INFORMATION FROM THE KOREAN MINISTRY OF FOOD AND DRUG SAFETY. SELECTED NUTRIENT FUNCTIONALITIES, INCLUDING THE ATTENUATION OF FATTY ACID-INDUCED LIPID ACCUMULATION AND LIPOPOLYSACCHARIDE-MEDIATED ACUTE INFLAMMATION WERE EVALUATED IN MOUSE MACROPHAGE RAW264.7 AND MOUSE HEPATOCYTE AML-12 CELLS. EFFECTS OF THE SELECTED NUTRIENTS ON IN VITRO HAT INHIBITION WERE ALSO EVALUATED. RESULTS: NITRIC OXIDE (NO) PRODUCTION CORRELATED WITH HAT ACTIVITY, WHICH WAS REGULATED BY THE AMINO ACIDS GROUP, SUGGESTING THAT AMINO ACIDS POTENTIALLY CONTRIBUTE TO THE ATTENUATION OF NO PRODUCTION VIA THE INHIBITION OF HAT ACTIVITY. UNSATURATED FATTY ACIDS TENDED TO ATTENUATE INFLAMMATION BY INHIBITING NO PRODUCTION, WHICH MAY BE ATTRIBUTABLE TO THE INHIBITION OF IN VITRO HAT ACTIVITY. IN CONTRAST TO WATER-SOLUBLE VITAMINS, THE LIPID-SOLUBLE VITAMINS SIGNIFICANTLY DECREASED NO PRODUCTION. WATER- AND LIPID-SOLUBLE VITAMINS BOTH EXHIBITED SIGNIFICANT INHIBITORY ACTIVITIES AGAINST HAT. IN ADDITION, CALCIUM AND MANGANESE SIGNIFICANTLY INHIBITED LIPID ACCUMULATION, NO PRODUCTION, AND HAT ACTIVITY. CONCLUSIONS: SEVERAL CANDIDATE NUTRIENTS AND THEIR FAMILY MEMBERS MAY HAVE ROLES IN THE PREVENTION OF DISEASES, INCLUDING HEPATIC STEATOSIS AND INFLAMMATION-RELATED DISEASES (I.E., NONALCOHOLIC STEATOHEPATITIS) VIA EPIGENETIC REGULATION. FURTHER STUDIES ARE WARRANTED TO DETERMINE WHICH SPECIFIC AMINO ACIDS, UNSATURATED FATTY ACIDS AND LIPID-SOLUBLE VITAMINS OR SPECIFIC MINERALS INFLUENCE THE DEVELOPMENT OF STEATOSIS AND INFLAMMATORY-RELATED DISEASES. 2023 12 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 13 4801 24 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 14 6471 34 TNF-ALPHA REGULATES DIABETIC MACROPHAGE FUNCTION THROUGH THE HISTONE ACETYLTRANSFERASE MOF. A CRITICAL COMPONENT OF WOUND HEALING IS THE TRANSITION FROM THE INFLAMMATORY PHASE TO THE PROLIFERATION PHASE TO INITIATE HEALING AND REMODELING OF THE WOUND. MACROPHAGES ARE CRITICAL FOR THE INITIATION AND RESOLUTION OF THE INFLAMMATORY PHASE DURING WOUND REPAIR. IN DIABETES, MACROPHAGES DISPLAY A SUSTAINED INFLAMMATORY PHENOTYPE IN LATE WOUND HEALING CHARACTERIZED BY ELEVATED PRODUCTION OF INFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA. PREVIOUS STUDIES HAVE SHOWN THAT AN ALTERED EPIGENETIC PROGRAM DIRECTS DIABETIC MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE, CONTRIBUTING TO A SUSTAINED INFLAMMATORY PHASE. MALES ABSENT ON THE FIRST (MOF) IS A HISTONE ACETYLTRANSFERASE (HAT) THAT HAS BEEN SHOWN BE A COACTIVATOR OF TNF-ALPHA SIGNALING AND PROMOTE NF-KAPPAB-MEDIATED GENE TRANSCRIPTION IN PROSTATE CANCER CELL LINES. BASED ON MOF'S ROLE IN TNF-ALPHA/NF-KAPPAB-MEDIATED GENE EXPRESSION, WE HYPOTHESIZED THAT MOF INFLUENCES MACROPHAGE-MEDIATED INFLAMMATION DURING WOUND REPAIR. WE USED MYELOID-SPECIFIC MOF-KNOCKOUT (LYZ2CRE MOFFL/FL) AND DIET-INDUCED OBESE (DIO) MICE TO DETERMINE THE FUNCTION OF MOF IN DIABETIC WOUND HEALING. MOF-DEFICIENT MICE EXHIBITED REDUCED INFLAMMATORY CYTOKINE GENE EXPRESSION. FURTHERMORE, WE FOUND THAT WOUND MACROPHAGES FROM DIO MICE HAD ELEVATED MOF LEVELS AND HIGHER LEVELS OF ACETYLATED HISTONE H4K16, MOF'S PRIMARY SUBSTRATE OF HAT ACTIVITY, ON THE PROMOTERS OF INFLAMMATORY GENES. WE FURTHER IDENTIFIED THAT MOF EXPRESSION COULD BE STIMULATED BY TNF-ALPHA AND THAT TREATMENT WITH ETANERCEPT, AN FDA-APPROVED TNF-ALPHA INHIBITOR, REDUCED MOF LEVELS AND IMPROVED WOUND HEALING IN DIO MICE. THIS REPORT IS THE FIRST TO OUR KNOWLEDGE TO DEFINE AN IMPORTANT ROLE FOR MOF IN REGULATING MACROPHAGE-MEDIATED INFLAMMATION IN WOUND REPAIR AND IDENTIFIES TNF-ALPHA INHIBITION AS A POTENTIAL THERAPY FOR THE TREATMENT OF CHRONIC INFLAMMATION IN DIABETIC WOUNDS. 2020 15 313 25 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 16 1383 28 DIABETES AND ITS CARDIOVASCULAR COMPLICATIONS: POTENTIAL ROLE OF THE ACETYLTRANSFERASE P300. DIABETES HAS BEEN SHOWN TO ACCELERATE VASCULAR SENESCENCE, WHICH IS ASSOCIATED WITH CHRONIC INFLAMMATION AND OXIDATIVE STRESS, BOTH IMPLICATED IN THE DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION. THIS CONDITION REPRESENTS THE INITIAL ALTERATION LINKING DIABETES TO RELATED CARDIOVASCULAR (CV) COMPLICATIONS. RECENTLY, IT HAS BEEN HYPOTHESISED THAT THE ACETYLTRANSFERASE, P300, MAY CONTRIBUTE TO ESTABLISHING AN EARLY VASCULAR SENESCENT PHENOTYPE, PLAYING A RELEVANT ROLE IN DIABETES-ASSOCIATED INFLAMMATION AND OXIDATIVE STRESS, WHICH DRIVE ENDOTHELIAL DYSFUNCTION. SPECIFICALLY, P300 CAN MODULATE VASCULAR INFLAMMATION THROUGH EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTORS ACETYLATION. INDEED, IT REGULATES THE INFLAMMATORY PATHWAY BY INTERACTING WITH NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS P65 SUBUNIT (NF-KAPPAB P65) OR BY INDUCING ITS ACETYLATION, SUGGESTING A CRUCIAL ROLE OF P300 AS A BRIDGE BETWEEN NF-KAPPAB P65 AND THE TRANSCRIPTIONAL MACHINERY. ADDITIONALLY, P300-MEDIATED EPIGENETIC MODIFICATIONS COULD BE UPSTREAM OF THE ACTIVATION OF INFLAMMATORY CYTOKINES, AND THEY MAY INDUCE OXIDATIVE STRESS BY AFFECTING THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). BECAUSE SEVERAL IN VITRO AND IN VIVO STUDIES SHED LIGHT ON THE POTENTIAL USE OF ACETYLTRANSFERASE INHIBITORS, A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE ROLE OF P300 IN DIABETIC VASCULAR DYSFUNCTION COULD HELP IN FINDING NEW STRATEGIES FOR THE CLINICAL MANAGEMENT OF CV DISEASES RELATED TO DIABETES. 2023 17 4455 29 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 18 1017 30 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 19 4974 26 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 20 2613 30 EPIGENETICS: DECIPHERING ITS ROLE IN DIABETES AND ITS CHRONIC COMPLICATIONS. 1. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS MIGHT REGULATE THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT, AND AFFECT HUMAN DISEASES, SUCH AS DIABETES AND ITS COMPLICATIONS. 2. CLINICAL TRIALS HAVE UNDERSCORED THE LONG LASTING BENEFICIAL EFFECTS OF STRICT GLYCAEMIC CONTROL FOR REDUCING THE PROGRESSION OF DIABETIC COMPLICATIONS. THEY HAVE ALSO SHOWN THAT DIABETIC COMPLICATIONS, SUCH AS DIABETIC NEPHROPATHY, A CHRONIC KIDNEY DISORDER, CAN CONTINUE EVEN AFTER BLOOD GLUCOSE NORMALIZATION, SUGGESTING A METABOLIC MEMORY OF THE PRIOR GLYCAEMIC STATE. 3. DYSREGULATION OF EPIGENETIC POST-TRANSCRIPTIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, INCLUDING HISTONE LYSINE METHYLATION, HAS BEEN IMPLICATED IN ABERRANT GENE REGULATION ASSOCIATED WITH THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS. GENOME-WIDE STUDIES HAVE SHOWN CELL-TYPE SPECIFIC CHANGES IN HISTONE METHYLATION PATTERNS UNDER DIABETIC CONDITIONS. IN ADDITION, STUDIES IN VASCULAR CELLS HAVE SHOWN LONG LASTING CHANGES IN EPIGENETIC MODIFICATIONS AT KEY INFLAMMATORY GENE PROMOTERS AFTER PRIOR EXPOSURE TO DIABETIC CONDITIONS, SUGGESTING A POSSIBLE MECHANISM FOR METABOLIC MEMORY. 4. RECENT STUDIES HAVE SHOWN ROLES FOR HISTONE METHYLATION, DNA METHYLATION, AS WELL AS MICRORNA IN DIABETIC NEPHROPATHY. WHETHER THESE EPIGENETIC FACTORS PLAY A ROLE IN METABOLIC MEMORY OF DIABETIC KIDNEY DISEASE IS LESS WELL UNDERSTOOD. 5. THE INCIDENCE OF DIABETES IS GROWING RAPIDLY, AS ALSO THE COST OF TREATING THE RESULTING COMPLICATIONS. A BETTER UNDERSTANDING OF METABOLIC MEMORY AND THE POTENTIAL INVOLVEMENT OF EPIGENETIC MECHANISMS IN THIS PHENOMENON COULD ENABLE THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS FOR THE TREATMENT AND/OR PREVENTION OF SUSTAINED DIABETIC COMPLICATIONS. 2011