1 4307 150 MICRORNA-30 MODULATES METABOLIC INFLAMMATION BY REGULATING NOTCH SIGNALING IN ADIPOSE TISSUE MACROPHAGES. BACKGROUND/OBJECTIVES: OBESITY IS A PANDEMIC DISORDER THAT IS CHARACTERIZED BY ACCUMULATION OF ADIPOSE TISSUE AND CHRONIC LOW-GRADE INFLAMMATION THAT IS DRIVEN PRIMARILY BY ADIPOSE TISSUE MACROPHAGES (ATMS). WHILE ATM POLARIZATION FROM PRO-(M1) TO ANTI-(M2) INFLAMMATORY PHENOTYPE INFLUENCES INSULIN SENSITIVITY AND ENERGY EXPENDITURE, THE MECHANISMS OF SUCH A SWITCH ARE UNCLEAR. IN THE CURRENT STUDY, WE IDENTIFIED EPIGENETIC PATHWAYS INCLUDING MICRORNAS (MIR) IN ATMS THAT REGULATE OBESITY-INDUCED INFLAMMATION. SUBJECTS/METHODS: MALE C57BL/6J MICE WERE FED NORMAL CHOW DIET (NCD) OR HIGH-FAT DIET (HFD) FOR 16 WEEKS TO DEVELOP LEAN AND DIET-INDUCED OBESE MICE, RESPECTIVELY. TRANSCRIPTOME MICROARRAYS, MICRORNA MICROARRAYS, AND MEDIP-SEQ WERE PERFORMED ON ATMS ISOLATED FROM VISCERAL FAT. PATHWAY ANALYSIS AND BONE MARROW-DERIVED MACROPHAGE (BMDM) TRANSFECTIONS FURTHER ALLOWED COMPUTATIONAL AND FUNCTIONAL ANALYSIS OF MIRNA-MEDIATED ATM POLARIZATION. RESULTS: ATMS FROM HFD-FED MICE WERE SKEWED TOWARD M1 INFLAMMATORY PHENOTYPE. CONCURRENTLY, THE EXPRESSION OF MIRS 30A-5P, 30C-5P, AND 30E-5P WAS DOWNREGULATED IN ATMS FROM HFD MICE WHEN COMPARED TO MICE FED NCD. THE MIR-30 FAMILY WAS SHOWN TO TARGET DELTA-LIKE-4, A NOTCH1 LIGAND, WHOSE EXPRESSION WAS INCREASED IN HFD ATMS. INHIBITION OF MIR-30 IN CONDITIONED BMDM TRIGGERED NOTCH1 SIGNALING, PRO-INFLAMMATORY CYTOKINE PRODUCTION, AND M1 MACROPHAGE POLARIZATION. IN ADDITION, DNA HYPERMETHYLATION WAS OBSERVED IN MIR30-ASSOCIATED CPG ISLANDS, SUGGESTING THAT HFD DOWNREGULATES MIR-30 THROUGH EPIGENETIC MODIFICATIONS. CONCLUSIONS: HFD-INDUCED OBESITY DOWNREGULATES MIR-30 BY DNA METHYLATION THEREBY INDUCING NOTCH1 SIGNALING IN ATMS AND THEIR POLARIZATION TO M1 MACROPHAGES. THESE FINDINGS IDENTIFY MIR-30 AS A REGULATOR OF PRO-INFLAMMATORY ATM POLARIZATION AND SUGGEST THAT MIR-30 MANIPULATION COULD BE A THERAPEUTIC TARGET FOR OBESITY-INDUCED INFLAMMATION. 2018 2 37 34 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 3 6874 26 [PROGRESS IN THE REGULATION OF ENERGY METABOLIC HOMEOSTASIS BY THE SWI/SNF COMPLEX SUBUNIT BAF60A]. METABOLIC SYNDROME IS A GLOBAL CHRONIC EPIDEMIC. ITS PATHOGENESIS IS DETERMINED BY GENETIC AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATION IS REPORTED TO REGULATE GENE EXPRESSION WITHOUT ALTERING ITS NUCLEOTIDE SEQUENCES. IN RECENT YEARS, EPIGENETIC MODIFICATION IS SENSITIVELY RESPONDED TO ENVIRONMENTAL SIGNALS, FURTHER AFFECTING THE GENE EXPRESSION AND SIGNALING TRANSDUCTION. AMONG THESE REGULATORS, CHROMATIN REMODELING SWI/SNF (SWITCH/SUCROSE NON FERMENTABLE, SWI/SNF) COMPLEX SUBUNIT BAF60A PLAYS AN IMPORTANT ROLE IN MAINTAINING ENERGY HOMEOSTASIS IN MAMMALS. IN THIS PAPER, WE DESCRIBED THE PATHOPHYSIOLOGICAL ROLES OF BAF60A IN MAINTAINING THE BALANCE OF ENERGY METABOLISM, INCLUDING LIPID METABOLISM, CHOLESTEROL METABOLISM, UREA METABOLISM, AS WELL AS THEIR RHYTHMICITY. THEREFORE, IN-DEPTH UNDERSTANDING OF BAF60A-ORCHESTRATED TRANSCRIPTIONAL NETWORK OF ENERGY METABOLISM WILL PROVIDE POTENTIAL THERAPEUTIC TARGETS AND RELIABLE THEORETICAL SUPPORTS FOR THE TREATMENT OF METABOLIC SYNDROME. 2021 4 701 41 BROWN FAT DNMT3B DEFICIENCY AMELIORATES OBESITY IN FEMALE MICE. OBESITY RESULTS FROM A CHRONIC ENERGY IMBALANCE DUE TO ENERGY INTAKE EXCEEDING ENERGY EXPENDITURE. ACTIVATION OF BROWN FAT THERMOGENESIS HAS BEEN SHOWN TO COMBAT OBESITY. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HAS EMERGED AS A KEY REGULATOR OF BROWN FAT THERMOGENIC FUNCTION. HERE WE AIMED TO STUDY THE ROLE OF DNMT3B, A DNA METHYLTRANSFERASE INVOLVED IN DE NOVO DNA METHYLATION, IN THE REGULATION OF BROWN FAT THERMOGENESIS AND OBESITY. WE FOUND THAT THE SPECIFIC DELETION OF DNMT3B IN BROWN FAT PROMOTES THE THERMOGENIC AND MITOCHONDRIAL PROGRAM IN BROWN FAT, ENHANCES ENERGY EXPENDITURE, AND DECREASES ADIPOSITY IN FEMALE MICE FED A REGULAR CHOW DIET. WITH A LEAN PHENOTYPE, THE FEMALE KNOCKOUT MICE ALSO EXHIBIT INCREASED INSULIN SENSITIVITY. IN ADDITION, DNMT3B DEFICIENCY IN BROWN FAT ALSO PREVENTS DIET-INDUCED OBESITY AND INSULIN RESISTANCE IN FEMALE MICE. INTERESTINGLY, OUR RNA-SEQ ANALYSIS REVEALED AN UPREGULATION OF THE PI3K-AKT PATHWAY IN THE BROWN FAT OF FEMALE DNMT3B KNOCKOUT MICE. HOWEVER, MALE DNMT3B KNOCKOUT MICE HAVE NO CHANGE IN THEIR BODY WEIGHT, SUGGESTING THE EXISTENCE OF SEXUAL DIMORPHISM IN THE BROWN FAT DNMT3B KNOCKOUT MODEL. OUR DATA DEMONSTRATE THAT DNMT3B PLAYS AN IMPORTANT ROLE IN THE REGULATION OF BROWN FAT FUNCTION, ENERGY METABOLISM AND OBESITY IN FEMALE MICE. 2021 5 2241 40 EPIGENETIC MODULATION IN PERIODONTITIS: INTERACTION OF ADIPONECTIN AND JMJD3-IRF4 AXIS IN MACROPHAGES. EMERGING EVIDENCE SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING SIGNALS DURING MACROPHAGE POLARIZATION AND INFLAMMATION. JMJD3, A JMJC FAMILY HISTONE DEMETHYLASE NECESSARY FOR M2 POLARIZATION IS ALSO REQUIRED FOR EFFECTIVE INDUCTION OF MULTIPLE M1 GENES BY LIPOPOLYSACCHARIDE (LPS). HOWEVER, THE EFFECTS OF JMJD3 TO INFLAMMATION IN THE CONTEXT OF OBESITY REMAINS UNKNOWN. TO ADDRESS THIS DEFICIENCY, WE FIRSTLY EXAMINED THE EXPRESSION OF JMJD3 IN MACROPHAGE ISOLATED FROM BONE MARROW AND ADIPOSE TISSUE OF DIET INDUCED OBESITY (DIO) MICE. THE RESULTS INDICATED THAT JMJD3 WAS DOWN-REGULATED IN OBESITY. ADIPONECTIN (APN), A FACTOR SECRETED BY ADIPOSE TISSUE WHICH IS DOWN-REGULATED IN OBESITY, FUNCTIONS TO SWITCH MACROPHAGE POLARIZATION FROM M1 TO M2, THEREBY ATTENUATING CHRONIC INFLAMMATION. INTRIGUINGLY, OUR RESULTS INDICATED THAT APN CONTRIBUTED TO JMJD3 UP-REGULATION, REDUCED MACROPHAGE INFILTRATION IN OBESE ADIPOSE TISSUE, AND ABOLISHED THE UP-REGULATION OF JMJD3 IN PERITONEAL MACROPHAGES ISOLATED FROM DIO MICE WHEN CHALLENGED WITH PORPHYROMONAS GINGIVALIS LPS (PG.LPS). TO ELUCIDATE THE INTERACTION OF APN AND JMJD3 INVOLVED IN MACROPHAGE TRANSFORMATION IN THE CONTEXT OF INFLAMMATION, WE DESIGNED THE LOSS AND GAIN-FUNCTION EXPERIMENTS OF APN IN VIVO WITH APN(-/-) MICE WITH EXPERIMENTAL PERIODONTITIS AND IN VITRO WITH MACROPHAGE ISOLATED FROM APN(-/-) MICE. FOR THE FIRST TIME, WE FOUND THAT APN CAN HELP TO REDUCE PERIODONTITIS-RELATED BONE LOSS, MODULATE JMJD3 AND IRF4 EXPRESSION, AND MACROPHAGE INFILTRATION. THEREFORE, IT CAN BE INFERRED THAT APN MAY CONTRIBUTE TO ANTI-INFLAMMATION MACROPHAGE POLARIZATION BY REGULATING JMJD3 EXPRESSION, WHICH PROVIDES A BASIS FOR MACROPHAGE-CENTERED EPIGENETIC THERAPEUTIC STRATEGIES. 2016 6 3359 35 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 7 1725 36 DYSREGULATION OF INFLAMMATION, OXIDATIVE STRESS, AND GLUCOSE METABOLISM-RELATED GENES AND MIRNAS IN VISCERAL ADIPOSE TISSUE OF WOMEN WITH TYPE 2 DIABETES MELLITUS. BACKGROUND HUMAN VISCERAL ADIPOSE TISSUE (VAT), NOW IDENTIFIED AS AN ENDOCRINE ORGAN, PLAYS A SIGNIFICANT ROLE IN IMPAIRED FASTING GLUCOSE AND DIABETES THROUGH THE DEREGULATED METABOLISM AND ADIPOGENESIS OF VISCERAL ADIPOCYTES IN OBESITY. OUR STUDY FOCUSES ON EXPLORING THE LINK BETWEEN INFLAMMATION, OXIDATIVE STRESS, AND GLUCOSE METABOLISM-ASSOCIATED GENES WITH CORRESPONDING MIRNAS IN HUMAN VISCERAL ADIPOCYTES AND VAT FROM INDIVIDUALS WITH GLUCOSE METABOLISM DISORDERS. MATERIAL AND METHODS WE EXAMINED THE EXPRESSION OF ATM, NFKB1, SOD2, INSR, AND TIGAR, ALONG WITH THEIR RELATED MIRNAS USING PCR, IN TWO CONTEXTS:1 - DURING THE THREE-STAGE VISCERAL ADIPOGENESIS UNDER NORMAL GLUCOSE LEVELS (5.5 MILLIMOLES), INTERMITTENT, AND CHRONIC HYPERGLYCEMIA (30 MILLIMOLES).2 - IN VISCERAL ADIPOSE TISSUE FROM SUBJECTS (34 F, 18 M) WITH NORMAL GLUCOSE METABOLISM, IMPAIRED FASTING GLUCOSE, AND TYPE 2 DIABETES MELLITUS. RESULTS BOTH CHRONIC AND INTERMITTENT HYPERGLYCEMIA SIMILARLY INFLUENCED ATM, NFKB1, TIGAR, SOD2, INSR GENE EXPRESSION IN VISCERAL ADIPOCYTES, WITH CORRESPONDING CHANGES IN A FEW TESTED MIRNAS (EG, LET-7G-5P, MIR-145-5P, MIR-21-5P). ANTHROPOMETRIC AND BIOCHEMICAL PARAMETERS LED US TO FOCUS ON FEMALE SUBJECTS. OUR RESULTS SHOWED TRANSACTIVATION OF NFKB1, TIGAR, MIR-10B-5P, MIR-132-3P, MIR-20A-5P, MIR-21-5P, AND MIR-26A-5P EXCLUSIVELY IN TYPE 2 DIABETES MELLITUS. UPREGULATED MOLECULES (EXCLUDING MIR-10B-5P AND MIR-20A-5P) POSITIVELY CORRELATED WITH GLUCOSE METABOLISM MARKERS. CONCLUSIONS THE GENES STUDIED MAY UNDERGO MIRNA INTERFERENCES AND HYPERGLYCEMIC MEMORY IN VISCERAL ADIPOCYTES UNDER HYPERGLYCEMIC CONDITIONS. VAT FROM WOMEN WITH TYPE 2 DIABETES MELLITUS, BUT NOT WITH IMPAIRED FASTING GLUCOSE, SHOWED TRANSACTIVATED MIRNAS AND A MOLECULAR DYSREGULATION OF TIGAR AND NFKB1, POSSIBLY ENHANCING INFLAMMATION, OXIDATIVE STRESS, AND DISRUPTED GLUCOSE METABOLISM. THESE FINDINGS HIGHLIGHT THE EPIGENETIC AND MOLECULAR DISTURBANCES IN VAT RELATED TO GLUCOSE METABOLISM ABNORMALITIES. HOWEVER, ADDITIONAL RESEARCH IS NECESSARY TO FURTHER UNDERSTAND THEIR BIOLOGICAL SIGNIFICANCE. 2023 8 3300 39 HIGH-FAT DIET REPROGRAMS THE EPIGENOME OF RAT SPERMATOZOA AND TRANSGENERATIONALLY AFFECTS METABOLISM OF THE OFFSPRING. OBJECTIVES: CHRONIC AND HIGH CONSUMPTION OF FAT CONSTITUTES AN ENVIRONMENTAL STRESS THAT LEADS TO METABOLIC DISEASES. WE HYPOTHESIZED THAT HIGH-FAT DIET (HFD) TRANSGENERATIONALLY REMODELS THE EPIGENOME OF SPERMATOZOA AND METABOLISM OF THE OFFSPRING. METHODS: F0-MALE RATS FED EITHER HFD OR CHOW DIET FOR 12 WEEKS WERE MATED WITH CHOW-FED DAMS TO GENERATE F1 AND F2 OFFSPRING. MOTILE SPERMATOZOA WERE ISOLATED FROM F0 AND F1 BREEDERS TO DETERMINE DNA METHYLATION AND SMALL NON-CODING RNA (SNCRNA) EXPRESSION PATTERN BY DEEP SEQUENCING. RESULTS: NEWBORN OFFSPRING OF HFD-FED FATHERS HAD REDUCED BODY WEIGHT AND PANCREATIC BETA-CELL MASS. ADULT FEMALE, BUT NOT MALE, OFFSPRING OF HFD-FED FATHERS WERE GLUCOSE INTOLERANT AND RESISTANT TO HFD-INDUCED WEIGHT GAIN. THIS PHENOTYPE WAS PERPETUATED IN THE F2 PROGENY, INDICATING TRANSGENERATIONAL EPIGENETIC INHERITANCE. THE EPIGENOME OF SPERMATOZOA FROM HFD-FED F0 AND THEIR F1 MALE OFFSPRING SHOWED COMMON DNA METHYLATION AND SMALL NON-CODING RNA EXPRESSION SIGNATURES. ALTERED EXPRESSION OF SPERM MIRNA LET-7C WAS PASSED DOWN TO METABOLIC TISSUES OF THE OFFSPRING, INDUCING A TRANSCRIPTOMIC SHIFT OF THE LET-7C PREDICTED TARGETS. CONCLUSION: OUR RESULTS PROVIDE INSIGHT INTO MECHANISMS BY WHICH HFD TRANSGENERATIONALLY REPROGRAMS THE EPIGENOME OF SPERM CELLS, THEREBY AFFECTING METABOLIC TISSUES OF OFFSPRING THROUGHOUT TWO GENERATIONS. 2016 9 888 23 CHRONIC DELTA(8)-THC EXPOSURE DIFFERENTLY AFFECTS HISTONE MODIFICATIONS IN THE ADOLESCENT AND ADULT RAT BRAIN. ADOLESCENCE REPRESENTS A VULNERABLE PERIOD FOR THE PSYCHIATRIC CONSEQUENCES OF DELTA9-TETRAHYDROCANNABINOL (DELTA(8)-THC) EXPOSURE, HOWEVER, THE MOLECULAR UNDERPINNINGS OF THIS VULNERABILITY REMAIN TO BE ESTABLISHED. HISTONE MODIFICATIONS ARE EMERGING AS IMPORTANT EPIGENETIC MECHANISMS INVOLVED IN THE ETIOPATHOGENESIS OF PSYCHIATRIC DISEASES, THUS, WE INVESTIGATED THE IMPACT OF CHRONIC DELTA(8)-THC EXPOSURE ON HISTONE MODIFICATIONS IN DIFFERENT BRAIN AREAS OF FEMALE RATS. WE CHECKED HISTONE MODIFICATIONS ASSOCIATED TO BOTH TRANSCRIPTIONAL REPRESSION (H3K9 DI- AND TRI-METHYLATION, H3K27 TRI-METHYLATION) AND ACTIVATION (H3K9 AND H3K14 ACETYLATION) AFTER ADOLESCENT AND ADULT CHRONIC DELTA(8)-THC EXPOSURE IN THE HIPPOCAMPUS, NUCLEUS ACCUMBENS, AND AMYGDALA. CHRONIC EXPOSURE TO INCREASING DOSES OF DELTA(8)-THC FOR 11 DAYS AFFECTED HISTONE MODIFICATIONS IN A REGION- AND AGE-SPECIFIC MANNER. THE PRIMARY EFFECT IN THE ADOLESCENT BRAIN WAS REPRESENTED BY CHANGES LEADING TO TRANSCRIPTIONAL REPRESSION, WHEREAS THE ONE OBSERVED AFTER ADULT TREATMENT LED TO TRANSCRIPTIONAL ACTIVATION. MOREOVER, ONLY IN THE ADOLESCENT BRAIN, THE PRIMARY EFFECT WAS FOLLOWED BY A HOMEOSTATIC RESPONSE TO COUNTERBALANCE THE DELTA(8)-THC-INDUCED REPRESSIVE EFFECT, EXCEPT IN THE AMYGDALA. THE PRESENCE OF A MORE COMPLEX RESPONSE IN THE ADOLESCENT BRAIN MAY BE PART OF THE MECHANISMS THAT MAKE THE ADOLESCENT BRAIN VULNERABLE TO DELTA(8)-THC ADVERSE EFFECTS. 2017 10 201 43 ACTIVATING TRANSCRIPTION FACTOR 3 PROTECTS AGAINST PRESSURE-OVERLOAD HEART FAILURE VIA THE AUTOPHAGY MOLECULE BECLIN-1 PATHWAY. ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3), A CAMP RESPONSE ELEMENT-BINDING PROTEIN/ATF FAMILY TRANSCRIPTION FACTORS MEMBER, HAS BEEN IMPLICATED IN THE CARDIOVASCULAR AND INFLAMMATORY SYSTEM AND IS RAPIDLY INDUCED BY ISCHEMIC-REPERFUSION INJURIES. WE PERFORMED TRANSVERSE AORTIC BANDING (TAB) EXPERIMENTS USING ATF3 GENE-DELETED MICE (ATF3(-/-)) AND WILD-TYPE (WT) MICE TO DETERMINE WHAT EFFECT IT MIGHT HAVE ON HEART FAILURE INDUCED BY PRESSURE OVERLOADING. COMPARED WITH THE WT MICE, ATF3(-/-) MICE WERE FOUND BY ECHOCARDIOGRAPHY TO HAVE DECREASED LEFT VENTRICULAR CONTRACTILITY WITH LOSS OF NORMAL CARDIAC HYPERTROPHIC REMODELING. THE ATF3(-/-) MICE HAD GREATER NUMBERS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-DEOXYURIDINE NICK-END LABELING-POSITIVE CELLS AND HIGHER LEVELS OF ACTIVATED CASPASE-3, AS WELL AS MORE APOPTOSIS. RESTORATION OF ATF3 EXPRESSION IN THE HEART OF ATF3(-/-) MICE BY ADENOVIRUS-INDUCED ATF3 TREATMENT SIGNIFICANTLY IMPROVED CARDIAC CONTRACTILITY AFTER TAB. THE RESULTS FROM MOLECULAR AND BIOCHEMICAL ANALYSES, INCLUDING CHROMATIN IMMUNE-PRECIPITATION AND IN VITRO /IN VIVO PROMOTER ASSAYS, SHOWED THAT ATF3 BOUND TO THE ATF/CAMP RESPONSE ELEMENT OF THE BECLIN-1 PROMOTER AND THAT ATF3 REDUCED AUTOPHAGY VIA SUPPRESSION OF THE BECLIN-1-DEPENDENT PATHWAY. FURTHERMORE, INFUSION OF TERT-BUTYLHYDROQUINONE (TBHQ), A SELECTIVE ATF3 INDUCER, INCREASED THE EXPRESSION OF ATF3 VIA THE NUCLEAR FACTOR ERYTHROID 2-RELATED TRANSCRIPTIONAL FACTOR, INHIBITED TAB-INDUCED CARDIAC DILATATION, AND INCREASED LEFT VENTRICULAR CONTRACTILITY, THEREBY RESCUING HEART FAILURE. OUR STUDY IDENTIFIED A NEW EPIGENETIC REGULATION MEDIATED BY THE STRESS-INDUCIBLE GENE ATF3 ON TAB-INDUCED CARDIAC DYSFUNCTION. THESE FINDINGS SUGGEST THAT THE ATF3 ACTIVATOR TBHQ MAY HAVE THERAPEUTIC POTENTIAL FOR THE TREATMENT OF PRESSURE-OVERLOAD HEART FAILURE INDUCED BY CHRONIC HYPERTENSION OR OTHER PRESSURE OVERLOAD MECHANISMS. 2014 11 3410 51 HOXA5 UNDERGOES DYNAMIC DNA METHYLATION AND TRANSCRIPTIONAL REPRESSION IN THE ADIPOSE TISSUE OF MICE EXPOSED TO HIGH-FAT DIET. BACKGROUND/OBJECTIVES: THE GENOMIC BASES OF THE ADIPOSE TISSUE ABNORMALITIES INDUCED BY CHRONIC POSITIVE CALORIE EXCESS HAVE BEEN ONLY PARTIALLY ELUCIDATED. WE ADOPTED A GENOME-WIDE APPROACH TO DIRECTLY TEST WHETHER LONG-TERM HIGH-FAT DIET (HFD) EXPOSURE AFFECTS THE DNA METHYLATION PROFILE OF THE MOUSE ADIPOSE TISSUE AND TO IDENTIFY THE FUNCTIONAL CONSEQUENCES OF THESE CHANGES. SUBJECTS/METHODS: WE HAVE USED EPIDIDYMAL FAT OF MICE FED EITHER HIGH-FAT (HFD) OR REGULAR CHOW (STD) DIET FOR 5 MONTHS AND PERFORMED GENOME-WIDE DNA METHYLATION ANALYSES BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). MOUSE HOMEOBOX (HOX) GENE DNA METHYLATION PCR, RT-QPCR AND BISULPHITE SEQUENCING ANALYSES WERE THEN PERFORMED. RESULTS: MICE FED THE HFD PROGRESSIVELY EXPANDED THEIR ADIPOSE MASS ACCOMPANIED BY A SIGNIFICANT DECREASE IN GLUCOSE TOLERANCE (P<0.001) AND INSULIN SENSITIVITY (P<0.05). MEDIP-SEQ DATA ANALYSIS REVEALED A UNIFORM DISTRIBUTION OF DIFFERENTIALLY METHYLATED REGIONS (DMR) THROUGH THE ENTIRE ADIPOCYTE GENOME, WITH A HIGHER NUMBER OF HYPERMETHYLATED REGIONS IN HFD MICE (P<0.005). THIS DIFFERENT METHYLATION PROFILE WAS ACCOMPANIED BY INCREASED EXPRESSION OF THE DNMT3A DNA METHYLTRANSFERASE (DNMT; P<0.05) AND THE METHYL-CPG-BINDING DOMAIN PROTEIN MBD3 (P<0.05) GENES IN HFD MICE. GENE ONTOLOGY ANALYSIS REVEALED THAT, IN THE HFD-TREATED MICE, THE HOX FAMILY OF DEVELOPMENT GENES WAS HIGHLY ENRICHED IN DIFFERENTIALLY METHYLATED GENES (P=0.008). TO VALIDATE THIS FINDING, HOXA5, WHICH IS IMPLICATED IN FAT TISSUE DIFFERENTIATION AND REMODELING, HAS BEEN SELECTED AND ANALYZED BY BISULPHITE SEQUENCING, CONFIRMING HYPERMETHYLATION IN THE ADIPOSE TISSUE FROM THE HFD MICE. HOXA5 HYPERMETHYLATION WAS ASSOCIATED WITH DOWNREGULATION OF HOXA5 MRNA AND PROTEIN EXPRESSION. FEEDING ANIMALS PREVIOUSLY EXPOSED TO THE HFD WITH A STANDARD CHOW DIET FOR TWO FURTHER MONTHS IMPROVED THE METABOLIC PHENOTYPE OF THE ANIMALS, ACCOMPANIED BY RETURN OF HOXA5 METHYLATION AND EXPRESSION LEVELS (P<0.05) TO VALUES SIMILAR TO THOSE OF THE CONTROL MICE MAINTAINED UNDER STANDARD CHOW. CONCLUSIONS: HFD INDUCES ADIPOSE TISSUE ABNORMALITIES ACCOMPANIED BY EPIGENETIC CHANGES AT THE HOXA5 ADIPOSE TISSUE REMODELING GENE. 2016 12 875 31 CHRONIC AND TRANSIENT HYPERGLYCEMIA INDUCES CHANGES IN THE EXPRESSION PATTERNS OF IL6 AND ADIPOQ GENES AND THEIR ASSOCIATED EPIGENETIC MODIFICATIONS IN DIFFERENTIATING HUMAN VISCERAL ADIPOCYTES. ADIPOKINES SECRETED BY HYPERTROPHIC VISCERAL ADIPOSE TISSUE (VAT) INSTIGATE LOW-GRADE INFLAMMATION, FOLLOWED BY HYPERGLYCEMIA (HG)-RELATED METABOLIC DISORDERS. THE LATTER MAY DEVELOP WITH THE PARTICIPATION OF EPIGENETIC MODIFICATIONS. OUR AIM WAS TO ASSESS HOW HG INFLUENCES SELECTED EPIGENETIC MODIFICATIONS AND THE EXPRESSION OF INTERLEUKIN 6 (IL-6) AND ADIPONECTIN (APN; GENE SYMBOL ADIPOQ) DURING THE ADIPOGENESIS OF HUMAN VISCERAL PREADIPOCYTES (HPA-V). ADIPOCYTES (ADS) WERE CHRONICALLY OR TRANSIENTLY HG-TREATED DURING THREE STAGES OF ADIPOGENESIS (PROLIFERATION, DIFFERENTIATION, MATURATION). WE MEASURED ADIPOKINE MRNA, PROTEIN, PROVEN OR PREDICTED MICRORNA EXPRESSION (RT-QPCR AND ELISA), AND ENRICHMENT OF H3K9/14AC, H3K4ME3, AND H3K9ME3 AT GENE PROMOTER REGIONS (CHROMATIN IMMUNOPRECIPITATION). IN CHRONIC HG, WE DETECTED DIFFERENT EXPRESSION PATTERNS OF THE STUDIED ADIPOKINES AT THE MRNA AND PROTEIN LEVELS. CHRONIC AND TRANSIENT HG-INDUCED CHANGES IN MIRNA (MIR-26A-5P, MIR-26B-5P, LET-7D-5P, LET-7E-5P, MIR-365A-3P, MIR-146A-5P) WERE MOSTLY CONVERGENT TO ALTERED IL-6 TRANSCRIPTION. ALTERATIONS IN HISTONE MARKS AT THE IL6 PROMOTER WERE ALSO IN AGREEMENT WITH IL-6 MRNA. THE OPEN CHROMATIN MARKS AT THE ADIPOQ PROMOTER MOSTLY REFLECTED THE APN TRANSCRIPTION DURING NG ADIPOGENESIS, WHILE, IN THE DIFFERENTIATION STAGE, HG-INDUCED CHANGES IN ALL STUDIED MARKS WERE IN LINE WITH APN MRNA LEVELS. IN SUMMARY, HG DYSREGULATED ADIPOKINE EXPRESSION, PROMOTING INFLAMMATION. EPIGENETIC CHANGES COEXISTED WITH ALTERED EXPRESSION OF ADIPOKINES, ESPECIALLY FOR IL-6; THEREFORE, EPIGENETIC MARKS INDUCED BY TRANSIENT HG MAY ACT AS EPI-MEMORY IN ADS. SUCH CHANGES IN THE EPIGENOME AND EXPRESSION OF ADIPOKINES COULD BE INSTRUMENTAL IN THE DEVELOPMENT OF INFLAMMATION AND METABOLIC DEREGULATION OF VAT. 2021 13 4355 41 MIR-30 FAMILY MIRNAS MEDIATE THE EFFECT OF CHRONIC SOCIAL DEFEAT STRESS ON HIPPOCAMPAL NEUROGENESIS IN MOUSE DEPRESSION MODEL. DEPRESSION IS A DEBILITATING PSYCHIATRIC DISORDER WITH A HIGH RATE OF RELAPSE AND A LOW RATE OF RESPONSE TO ANTIDEPRESSANT TREATMENT. THERE IS A DEARTH OF NEW ANTIDEPRESSANTS DUE TO AN INCOMPLETE UNDERSTANDING OF THE MOLECULAR MECHANISMS INVOLVED IN ITS ETIOPATHOLOGY. CHRONIC STRESS APPEARS TO BE ONE OF THE FOREMOST UNDERLYING CAUSES OF DEPRESSION. STUDIES IN ANIMAL MODELS IN THE PAST DECADE HAVE IMPLICATED EPIGENETIC MECHANISMS IN MEDIATING THE NEGATIVE EFFECTS OF CHRONIC STRESSFUL EVENTS ON THE PROGRESSION/MANIFESTATION OF DEPRESSION AND OTHER CO-MORBID NEUROPSYCHIATRIC DISORDERS. HOWEVER, NON-CODING RNAS, ANOTHER LAYER OF EPIGENETIC REGULATION IS RELATIVELY LESS STUDIED IN DEPRESSION. HERE, USING THE CHRONIC SOCIAL DEFEAT STRESS (CSDS)-INDUCED DEPRESSION MODEL, WE HYPOTHESIZED DYSREGULATION IN MIRNA-MRNA NETWORKS IN THE NEUROGENIC DENTATE GYRUS (DG) REGION OF MALE C57BL/6 MICE. AMONG SEVERAL DYSREGULATED MIRNAS IDENTIFIED VIA MIRNA ARRAYS, THE MOST STRIKING FINDING WAS THE DOWNREGULATION OF MIRNAS OF THE MIR-30 FAMILY IN STRESSED/DEFEATED MICE. TO INVESTIGATE MIRNAS IN THE DG-RESIDENT NEURAL STEM/PROGENITOR CELLS (NSCS/NPCS), WE USED THE IN VITRO NEUROSPHERE CULTURE, WHERE PROLIFERATING NSCS/NPCS WERE SUBJECTED TO DIFFERENTIATION. AMONG SEVERAL DIFFERENTIALLY EXPRESSED MIRNAS, WE OBSERVED AN UPREGULATION OF MIR-30 FAMILY MIRNAS UPON DIFFERENTIATION. TO SEARCH FOR THE GENE TARGETS OF THESE MIRNAS, WE PERFORMED GENE ARRAYS FOLLOWED BY BIOINFORMATICS ANALYSIS, MIRNA MANIPULATIONS AND LUCIFERASE ASSAYS. OUR RESULTS SUGGEST THAT MIR-30 FAMILY MIRNAS MEDIATE CHRONIC STRESS-INDUCED DEPRESSION-LIKE PHENOTYPE BY ALTERING HIPPOCAMPAL NEUROGENESIS AND NEUROPLASTICITY VIA CONTROLLING THE EPIGENETIC AND TRANSCRIPTION REGULATORS SUCH AS MLL3 AND RUNX1; AND CELL SIGNALING REGULATORS LIKE SOCS3, PPP3R1, GPR125, AND NRP1. 2019 14 4017 41 LOW-DOSE HYDRALAZINE REDUCES ALBUMINURIA AND GLOMERULOSCLEROSIS IN A MOUSE MODEL OF OBESITY-RELATED CHRONIC KIDNEY DISEASE. AIM: TO DETERMINE, USING A MOUSE MODEL OF OBESITY, WHETHER LOW-DOSE HYDRALAZINE PREVENTS OBESITY-RELATED CHRONIC KIDNEY DISEASE (CKD). METHODS: FROM 8 WEEKS OF AGE, MALE C57BL/6 MICE RECEIVED A HIGH-FAT DIET (HFD) OR CHOW, WITH OR WITHOUT LOW-DOSE HYDRALAZINE (25 MG/L) IN DRINKING WATER, FOR 24 WEEKS. BIOMETRIC AND METABOLIC VARIABLES, RENAL FUNCTION AND STRUCTURAL CHANGES, RENAL GLOBAL DNA METHYLATION, DNA METHYLATION PROFILE AND MARKERS OF RENAL FIBROSIS, INJURY, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED. RESULTS: THE HFD-FED MICE DEVELOPED OBESITY, WITH GLUCOSE INTOLERANCE, HYPERINSULINAEMIA AND DYSLIPIDAEMIA. OBESITY INCREASED ALBUMINURIA AND GLOMERULOSCLEROSIS, WHICH WERE SIGNIFICANTLY AMELIORATED BY LOW-DOSE HYDRALAZINE IN THE ABSENCE OF A BLOOD PRESSURE-LOWERING EFFECT. OBESITY INCREASED RENAL GLOBAL DNA METHYLATION AND THIS WAS ATTENUATED BY LOW-DOSE HYDRALAZINE. HFD-INDUCED CHANGES IN METHYLATION OF INDIVIDUAL LOCI WERE ALSO SIGNIFICANTLY REVERSED BY LOW-DOSE HYDRALAZINE. OBESE MICE DEMONSTRATED INCREASED MARKERS OF KIDNEY FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS, BUT THESE MARKERS WERE NOT SIGNIFICANTLY IMPROVED BY HYDRALAZINE. CONCLUSION: LOW-DOSE HYDRALAZINE AMELIORATED HFD-INDUCED ALBUMINURIA AND GLOMERULOSCLEROSIS, INDEPENDENT OF ALTERATIONS IN BIOMETRIC AND METABOLIC VARIABLES OR BLOOD PRESSURE REGULATION. ALTHOUGH THE PRECISE MECHANISM OF RENOPROTECTION IN OBESITY IS UNCLEAR, AN EPIGENETIC BASIS MAY BE IMPLICATED. THESE DATA SUPPORT REPURPOSING HYDRALAZINE AS A NOVEL THERAPY TO PREVENT CKD PROGRESSION IN OBESE PATIENTS. 2022 15 240 48 ADIPOCYTE EXPRESSION OF SLC19A1 LINKS DNA HYPERMETHYLATION TO ADIPOSE TISSUE INFLAMMATION AND INSULIN RESISTANCE. CONTEXT: INSULIN RESISTANCE (IR) IS PROMOTED BY A CHRONIC LOW-GRADE INFLAMMATION IN WHITE ADIPOSE TISSUE (WAT). THE LATTER MIGHT BE REGULATED THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION. THE ONE CARBON CYCLE (1CC) IS A CENTRAL METABOLIC PROCESS GOVERNING DNA METHYLATION. OBJECTIVE: TO IDENTIFY ADIPOCYTE-EXPRESSED 1CC GENES LINKED TO WAT INFLAMMATION, IR, AND THEIR CAUSAL ROLE. DESIGN: COHORT STUDY. SETTING: OUTPATIENT ACADEMIC CLINIC. PARTICIPANTS: OBESE AND NONOBESE SUBJECTS. METHODS: GENE EXPRESSION AND DNA METHYLATION ARRAYS WERE PERFORMED IN SUBCUTANEOUS WAT AND ISOLATED ADIPOCYTES. IN IN VITRO DIFFERENTIATED HUMAN ADIPOCYTES, GENE KNOCKDOWN WAS ACHIEVED BY SMALL INTERFERING RNA, AND ANALYSES INCLUDED MICROARRAY, QUANTITATIVE POLYMERASE CHAIN REACTION, DNA METHYLATION BY ENZYME-LINKED IMMUNOSORBENT ASSAY AND PYROSEQUENCING, PROTEIN SECRETION BY ENZYME-LINKED IMMUNOSORBENT ASSAY, TARGETED METABOLOMICS, AND LUCIFERASE REPORTER AND THERMAL SHIFT ASSAYS. MAIN OUTCOME MEASURES: EFFECTS ON ADIPOCYTE INFLAMMATION. RESULTS: IN ADIPOCYTES FROM OBESE INDIVIDUALS, GLOBAL DNA HYPERMETHYLATION WAS ASSOCIATED POSITIVELY WITH GENE EXPRESSION OF PROINFLAMMATORY PATHWAYS. AMONG THE 1CC GENES, IR IN VIVO AND PROINFLAMMATORY GENE EXPRESSION IN WAT WERE MOST STRONGLY AND INVERSELY ASSOCIATED WITH SLC19A1, A GENE ENCODING A MEMBRANE FOLATE CARRIER. SLC19A1 KNOCKDOWN IN HUMAN ADIPOCYTES PERTURBED INTRACELLULAR 1CC METABOLISM, INDUCED GLOBAL DNA HYPERMETHYLATION, AND INCREASED EXPRESSION OF PROINFLAMMATORY GENES. SEVERAL CPG LOCI LINKED SLC19A1 TO INFLAMMATION; VALIDATION STUDIES WERE FOCUSED ON THE CHEMOKINE C-C MOTIF CHEMOKINE LIGAND 2 (CCL2) IN WHICH METHYLATION IN THE PROMOTER (CG12698626) REGULATED CCL2 EXPRESSION AND CCL2 SECRETION THROUGH ALTERED TRANSCRIPTIONAL ACTIVITY. CONCLUSIONS: REDUCED SLC19A1 EXPRESSION IN HUMAN ADIPOCYTES INDUCES DNA HYPERMETHYLATION, RESULTING IN INCREASED EXPRESSION OF SPECIFIC PROINFLAMMATORY GENES, INCLUDING CCL2. THIS CONSTITUTES AN EPIGENETIC MECHANISM THAT MIGHT LINK DYSFUNCTIONAL ADIPOCYTES TO WAT INFLAMMATION AND IR. 2018 16 241 38 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY. 2021 17 6221 32 THE LANDSCAPE OF HISTONE MODIFICATIONS IN A HIGH-FAT DIET-INDUCED OBESE (DIO) MOUSE MODEL. TYPE 2 DIABETES (T2D) IS A MAJOR CHRONIC HEALTHCARE CONCERN WORLDWIDE. EMERGING EVIDENCE SUGGESTS THAT A HISTONE-MODIFICATION-MEDIATED EPIGENETIC MECHANISM UNDERLIES T2D. NEVERTHELESS, THE DYNAMICS OF HISTONE MARKS IN T2D HAVE NOT YET BEEN CAREFULLY ANALYZED. USING A MASS SPECTROMETRY-BASED LABEL-FREE AND CHEMICAL STABLE ISOTOPE LABELING QUANTITATIVE PROTEOMIC APPROACH, WE SYSTEMATICALLY PROFILED LIVER HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) IN A PREDIABETIC HIGH-FAT DIET-INDUCED OBESE (DIO) MOUSE MODEL. WE IDENTIFIED 170 HISTONE MARKS, 30 OF WHICH WERE PREVIOUSLY UNKNOWN. INTERESTINGLY, ABOUT 30% OF THE HISTONE MARKS IDENTIFIED IN DIO MOUSE LIVER BELONGED TO A SET OF RECENTLY REPORTED LYSINE ACYLATION MODIFICATIONS, INCLUDING PROPIONYLATION, BUTYRYLATION, MALONYLATION, AND SUCCINYLATION, SUGGESTING POSSIBLE ROLES OF THESE NEWLY IDENTIFIED HISTONE ACYLATIONS IN DIABETES AND OBESITY. THESE HISTONE MARKS WERE DETECTED WITHOUT PRIOR AFFINITY ENRICHMENT WITH AN ANTIBODY, DEMONSTRATING THAT THE HISTONE ACYLATION MARKS ARE PRESENT AT REASONABLY HIGH STOICHIOMETRY. FIFTEEN HISTONE MARKS DIFFERED IN ABUNDANCE IN DIO MOUSE LIVER COMPARED WITH LIVER FROM CHOW-FED MICE IN LABEL-FREE QUANTIFICATION, AND SIX HISTONE MARKS IN STABLE ISOTOPE LABELING QUANTIFICATION. ANALYSIS OF HEPATIC HISTONE MODIFICATIONS FROM METFORMIN-TREATED DIO MICE REVEALED THAT METFORMIN, A DRUG WIDELY USED FOR T2D, COULD REVERSE DIO-STIMULATED HISTONE H3K36ME2 IN PREDIABETES, SUGGESTING THAT THIS MARK IS LIKELY ASSOCIATED WITH T2D DEVELOPMENT. OUR STUDY THUS OFFERS A COMPREHENSIVE LANDSCAPE OF HISTONE MARKS IN A PREDIABETIC MOUSE MODEL, PROVIDES A RESOURCE FOR STUDYING EPIGENETIC FUNCTIONS OF HISTONE MODIFICATIONS IN OBESITY AND T2D, AND SUGGEST A NEW EPIGENETIC MECHANISM FOR THE PHYSIOLOGICAL FUNCTION OF METFORMIN. 2017 18 3155 32 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 19 6887 38 [ROLE OF METAFLAMMATION AS A SYSTEMIC MANIFESTATION OF METABOLIC DISEASES]. VISCERAL OBESITY AS A COMPONENT OF THE METABOLIC SYNDROME IS CHARACTERIZED BY SYSTEMIC AND LOCAL INFLAMMATION, WHICH CAN BE QUANTIFIED IN ORGANS (METAFLAMMATION). THIS PROCESS CAN BE REGARDED AS A CHRONIC, STERILE, AND LOW-GRADE STATE OF INFLAMMATION WITHOUT INFECTION, TRAUMA, TUMOR OR AUTOIMMUNITY. IT IS CAUSED BY AN INFLAMMATION OF THE VISCERAL ADIPOSE TISSUE (ADIPOSE INFLAMMATION OR ADIPOFLAMMATION) DUE TO ADIPOCYTE HYPERTROPHY AND HYPERPLASIA WITH INCREASED INFILTRATION BY MONOCYTES AND MACROPHAGES. IMPORTANT IS THE PRESENCE OF PROINFLAMMATORY, SO-CALLED POLARIZED M1 MACROPHAGES THAT ARE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) AND LIPOPOLYSACCHARIDES (LPS) WITH SECRETION OF INTERLEUKIN (IL)-6, TUMOR NECROSIS FACTOR (TNF) AND IL?1. IN CONTRAST, THE ANTI-INFLAMMATORY, SO-CALLED POLARIZED M2 MACROPHAGES INDUCED BY IL?4 AND IL-13 WITH SECRETION OF IL?8 AND IL-10 DECREASE. IN ADDITION, THE SECRETED ADIPOKINE PATTERN CHANGES FROM ANTI-INFLAMMATORY TO PROINFLAMMATORY. ADIPOCYTE NECROSIS, LOCAL HYPOXIA, DYSREGULATED AUTOPHAGY, ACTIVATION OF INFLAMMASOMES, MODULATION OF TOLL-LIKE RECEPTORS, AND EPIGENETIC FACTORS PLAY A COMPLEX ROLE. THIS MECHANISM RESULTS IN LOCAL INSULIN RESISTANCE AND SUBSEQUENTLY A SYSTEMIC INSULIN RESISTANCE OF PERIPHERAL ORGANS AS WELL AS A SPILLOVER OF LOCAL MEDIATORS OF INFLAMMATION INTO THE SYSTEMIC CIRCULATION (MEASURED AS OBESITY C?REACTIVE PROTEIN, CRP). THE ACTIVATION OF INFLAMMATORY SIGNAL TRANSDUCTION CASCADES LEADS TO INHIBITORY PHOSPHORYLATION OF THE INSULIN SIGNALING PATHWAY AND A WEAKENING OF THE EFFECT OF INSULIN. IN PARALLEL, ECTOPIC LIPID ACCUMULATION OCCURS IN THE LIVER, MUSCULATURE, PANCREAS, PERICARDIUM AND LUNGS. DIACYLGLYCEROL (DAG) ACTIVATES SPECIFIC ISOFORMS OF PROTEIN KINASE C (EPSILON IN THE LIVER AND TAU IN THE MUSCULATURE), WHICH IN TURN LEAD TO INHIBITION OF THE INSULIN SIGNALING PATHWAY. INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES MELLITUS IS AN INFLAMMATORY DISEASE. THE AIM OF FUTURE TRANSLATIONAL APPROACHES IS AN ANTI-INFLAMMATORY, MOLECULARLY INDIVIDUALIZED (PRECISION MEDICINE) TREATMENT IN ADIPOSE TISSUE (TARGETED THERAPY) AND IN ORGANS OF INSULIN RESISTANCE. 2023 20 4034 37 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021