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 2 240 42 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 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 3353 25 HISTONE DEMETHYLASES REGULATE ADIPOCYTE THERMOGENESIS. ADIPOCYTES PLAY A PIVOTAL ROLE IN THE REGULATION OF ENERGY METABOLISM. WHILE WHITE ADIPOCYTE STORES ENERGY, BROWN ADIPOCYTE DISSIPATES ENERGY BY PRODUCING HEAT. IN ADDITION, ANOTHER TYPE OF HEAT-PRODUCING ADIPOCYTE, BEIGE ADIPOCYTE, EMERGES IN WHITE ADIPOSE TISSUE IN RESPONSE TO CHRONIC COLDNESS. THIS PHENOTYPIC ADAPTATION TO THE COLD ENVIRONMENT IS CONSIDERED TO BE ATTRIBUTED TO THE EPIGENETIC MODIFICATIONS. HISTONE METHYLATION IS A CHEMICALLY STABLE EPIGENETIC MODIFICATION AND THUS A PROPER MECHANISM FOR LONG-LASTING CELLULAR MEMORY. SEVERAL HISTONE METHYL-MODIFYING ENZYMES SUCH AS EHMT1, JMJD1A, JMJD3, AND LSD1 ARE REPORTED TO BE INVOLVED IN THE BEIGE ADIPOSE CELL FATE DETERMINATION. AMONG THESE, A HISTONE DEMETHYLASE JMJD1A SENSES COLD ENVIRONMENT BY BEING PHOSPHORYLATED AT S265 IN RESPONSE TO BETA-ADRENERGIC RECEPTOR STIMULATION. PHOSPHORYLATED JMJD1A REGULATES BOTH ACUTE AND COLD THERMOGENESIS. UNDER ACUTE COLDNESS, PHOSPHORYLATED JMJD1A FORMS A COMPLEX WITH CHROMATIN REMODELER SWI/SNF AND DNA-BOUND PPARGAMMA, WHICH RECRUITS JMJD1A TO THE TARGET GENOMIC REGIONS IN BROWN ADIPOCYTE. THIS COMPLEX FORMATION, IN TURN, INDUCES THE EXPRESSION OF TARGET GENES BY BRINGING THE ENHANCER AND THE PROMOTER INTO CLOSE PROXIMITY. DURING CHRONIC COLDNESS, PHOSPHORYLATED JMJD1A REGULATES BEIGE ADIPOGENESIS THROUGH A TWO-STEP MECHANISM. IN THE FIRST STEP, PHOSPHORYLATED JMJD1A IS RECRUITED TO THE REGULATORY REGIONS OF TARGET GENES BY FORMING A COMPLEX WITH PRDM16, PGC1ALPHA, AND DNA-BOUND PPARGAMMA. IN THE SECOND STEP, JMJD1A DEMETHYLATES HISTONE H3K9ME2 AND INDUCES STABLE EXPRESSION OF BEIGE-SELECTIVE GENES. THE PHENOTYPIC ANALYSES OF JMJD1A-NULL MICE AND NON-PHOSPHORYLATED MUTANT S265A JMJD1A KNOCK-IN MICE INDICATE THAT JMJD1A IS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF OBESITY-RELATED DISEASES INCLUDING METABOLIC SYNDROME AND TYPE 2 DIABETES. 2018 5 4034 26 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 6 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 7 5332 21 PYRUVATE DEHYDROGENASE KINASE 1 AND 2 DEFICIENCY REDUCES HIGH-FAT DIET-INDUCED HYPERTROPHIC OBESITY AND INHIBITS THE DIFFERENTIATION OF PREADIPOCYTES INTO MATURE ADIPOCYTES. OBESITY IS NOW RECOGNIZED AS A DISEASE. THIS STUDY REVEALED A NOVEL ROLE FOR PYRUVATE DEHYDROGENASE KINASE (PDK) IN DIET-INDUCED HYPERTROPHIC OBESITY. MICE WITH GLOBAL OR ADIPOSE TISSUE-SPECIFIC PDK2 DEFICIENCY WERE PROTECTED AGAINST DIET-INDUCED OBESITY. THE WEIGHT OF ADIPOSE TISSUES AND THE SIZE OF ADIPOCYTES WERE REDUCED. ADIPOCYTE-SPECIFIC PDK2 DEFICIENCY SLIGHTLY INCREASED INSULIN SENSITIVITY IN HFD-FED MICE. IN STUDIES WITH 3T3-L1 PREADIPOCYTES, PDK2 AND PDK1 EXPRESSION WAS STRONGLY INCREASED DURING ADIPOGENESIS. EVIDENCE WAS FOUND FOR EPIGENETIC INDUCTION OF BOTH PDK1 AND PDK2. GAIN- AND LOSS-OF-FUNCTION STUDIES WITH 3T3-L1 CELLS REVEALED A CRITICAL ROLE FOR PDK1/2 IN ADIPOCYTE DIFFERENTIATION AND LIPID ACCUMULATION. PDK1/2 INDUCTION DURING DIFFERENTIATION WAS ALSO ACCOMPANIED BY INCREASED EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF1ALPHA) AND ENHANCED LACTATE PRODUCTION, BOTH OF WHICH WERE ABSENT IN THE CONTEXT OF PDK1/2 DEFICIENCY. EXOGENOUS LACTATE SUPPLEMENTATION INCREASED THE STABILITY OF HIF1ALPHA AND PROMOTED ADIPOGENESIS. PDK1/2 OVEREXPRESSION-MEDIATED ADIPOGENESIS WAS ABOLISHED BY HIF1ALPHA INHIBITION, SUGGESTING A ROLE FOR THE PDK-LACTATE-HIF1ALPHA AXIS DURING ADIPOGENESIS. IN HUMAN ADIPOSE TISSUE, THE EXPRESSION OF PDK1/2 WAS POSITIVELY CORRELATED WITH THAT OF THE ADIPOGENIC MARKER PPARGAMMA AND INVERSELY CORRELATED WITH OBESITY. SIMILARLY, PDK1/2 EXPRESSION IN MOUSE ADIPOSE TISSUE WAS DECREASED BY CHRONIC HIGH-FAT DIET FEEDING. WE CONCLUDE THAT PDK1 AND 2 ARE NOVEL REGULATORS OF ADIPOGENESIS THAT PLAY CRITICAL ROLES IN OBESITY. 2021 8 3875 22 KDM2A DEFICIENCY IN MACROPHAGES ENHANCES THERMOGENESIS TO PROTECT MICE AGAINST HFD-INDUCED OBESITY BY ENHANCING H3K36ME2 AT THE PPARG LOCUS. KDM2A CATALYZES H3K36ME2 DEMETHYLATION TO PLAY AN INTRIGUING EPIGENETIC REGULATORY ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HEREIN WE FOUND THAT MYELOID-SPECIFIC KNOCKOUT OF KDM2A (LYSM-CRE-KDM2A(F/F), KDM2A(-/-)) PROMOTED MACROPHAGE M2 PROGRAM BY REPROGRAMING METABOLIC HOMEOSTASIS THROUGH ENHANCING FATTY ACID UPTAKE AND LIPOLYSIS. KDM2A(-/-) INCREASED H3K36ME2 LEVELS AT THE PPARG LOCUS ALONG WITH AUGMENTED CHROMATIN ACCESSIBILITY AND STAT6 RECRUITMENT, WHICH RENDERED MACROPHAGES WITH PREFERENTIAL M2 POLARIZATION. THEREFORE, THE KDM2A(-/-) MICE WERE HIGHLY PROTECTED FROM HIGH-FAT DIET (HFD)-INDUCED OBESITY, INSULIN RESISTANCE, AND HEPATIC STEATOSIS, AND FEATURED BY THE REDUCED ACCUMULATION OF ADIPOSE TISSUE MACROPHAGES AND REPRESSED CHRONIC INFLAMMATION FOLLOWING HFD CHALLENGE. PARTICULARLY, KDM2A(-/-) MACROPHAGES PROVIDED A MICROENVIRONMENT IN FAVOR OF THERMOGENESIS. UPON HFD OR COLD CHALLENGE, THE KDM2A(-/-) MICE MANIFESTED HIGHER CAPACITY FOR INDUCING ADIPOSE BROWNING AND BEIGING TO PROMOTE ENERGY EXPENDITURE. COLLECTIVELY, OUR FINDINGS DEMONSTRATE THE IMPORTANCE OF KDM2A-MEDIATED H3K36 DEMETHYLATION IN ORCHESTRATING MACROPHAGE POLARIZATION, PROVIDING NOVEL INSIGHT THAT TARGETING KDM2A IN MACROPHAGES COULD BE A VIABLE THERAPEUTIC APPROACH AGAINST OBESITY AND INSULIN RESISTANCE. 2021 9 2301 22 EPIGENETIC REGULATION OF BEIGE ADIPOCYTE FATE BY HISTONE METHYLATION. ADIPOSE TISSUE HARBORS PLASTICITY TO ADAPT TO ENVIRONMENTAL THERMAL CHANGES. WHILE BROWN ADIPOCYTE IS A THERMOGENIC CELL WHICH PRODUCES HEAT ACUTELY IN RESPONSE TO COLD STIMULI, BEIGE (OR BRITE) ADIPOCYTE IS AN INDUCIBLE FORM OF THERMOGENIC ADIPOCYTES WHICH EMERGES IN THE WHITE ADIPOSE DEPOTS IN RESPONSE TO CHRONIC COLD EXPOSURE. SUCH ADAPTABILITY OF ADIPOCYTES IS REGULATED BY EPIGENETIC MECHANISMS. AMONG THEM, HISTONE METHYLATION IS CHEMICALLY STABLE AND THUS IS AN APPROPRIATE EPIGENETIC MARK FOR MEDIATING CELLULAR MEMORY TO INDUCE AND MAINTAIN THE BEIGE ADIPOCYTE CHARACTERISTICS. THE ENZYMES THAT CATALYZE THE METHYLATION OR DEMETHYLATION OF H3K27 AND H3K9 REGULATE BROWN ADIPOCYTE BIOGENESIS THROUGH THEIR CATALYTIC ACTIVITY-DEPENDENT AND -INDEPENDENT MECHANISMS. RESOLVING THE BIVALENCY OF H3K4ME3 AND H3K27ME3 AS WELL AS "OPENING" THE CHROMATIN STRUCTURE BY DEMETHYLATION OF H3K9 BOTH MEDIATE BEIGE ADIPOGENESIS. IN ADDITION, IT IS RECENTLY REPORTED THAT MAINTENANCE OF BEIGE ADIPOCYTE, BEIGE-TO-WHITE TRANSITION, AND CELLULAR MEMORY OF PRIOR COLD EXPOSURE IN BEIGE ADIPOCYTE ARE ALSO REGULATED BY HISTONE METHYLATION. A FURTHER UNDERSTANDING OF THE EPIGENETIC MECHANISM OF BEIGE ADIPOCYTE BIOGENESIS WOULD UNRAVEL THE MECHANISM OF THE CELLULAR MEMORY OF ENVIRONMENTAL STIMULI AND PROVIDE A NOVEL THERAPEUTICS FOR THE METABOLIC DISORDERS SUCH AS OBESITY AND DIABETES THAT ARE INFLUENCED BY ENVIRONMENTAL FACTORS. 2019 10 4307 32 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 11 3237 26 HEPATIC COX-2 EXPRESSION PROTECTS MICE FROM AN ALCOHOL-HIGH FAT DIET-INDUCED METABOLIC DISORDER BY INVOLVING PROTEIN ACETYLATION RELATED ENERGY METABOLISM. PURPOSE: A DIET HIGH IN FAT AND ETHANOL OFTEN RESULTS IN CHRONIC METABOLIC DISORDER, HEPATIC STEATOSIS, AND LIVER INFLAMMATION. CONSTITUTIVE HEPATIC CYCLOOXYGENASE-2 (COX-2) EXPRESSION COULD PROTECT FROM HIGH FAT-INDUCED METABOLISM DISTURBANCE IN A MURINE MODEL. IN THIS STUDY, WE EXPLORED THE INFLUENCE OF HCOX-2 TRANSGENIC [TG] TO HIGH FAT WITH ETHANOL-INDUCED METABOLIC DISORDER AND LIVER INJURY USING A MOUSE ANIMAL MODEL. METHODS: 12-WEEK-OLD MALE HEPATIC HCOX-2 TRANSGENIC (TG) OR WILD TYPE MICE (WT) WERE FED EITHER A HIGH FAT AND ETHANOL LIQUID DIET (HF+ETH) OR A REGULAR CONTROL DIET (RCD) FOR 5 WEEKS (FOUR GROUPS: RCD/WT, RCD/TG; HF+ETH/TG, HF+ETH/WT). WE ASSESSED METABOLIC BIOMARKERS, CYTOKINE PROFILES, HISTOMORPHOLOGY, AND GENE EXPRESSION TO STUDY THE IMPACT OF PERSISTENT HEPATIC COX-2 EXPRESSION ON DIET-INDUCED LIVER INJURY. RESULTS: IN THE HF+ETH DIET, CONSTITUTIVELY HEPATIC HUMAN COX-2 EXPRESSION PROTECTS MICE FROM BODY WEIGHT GAIN AND WHITE ADIPOSE TISSUE ACCUMULATION, ACCOMPANIED BY IMPROVED IPGTT RESPONSE, SERUM TRIGLYCERIDE/CHOLESTEROL LEVELS, AND LOWER LEVELS OF SERUM AND LIVER INFLAMMATORY CYTOKINES. HISTOLOGICALLY, HCOX-2 MICE SHOWED DECREASED HEPATIC LIPID DROPLETS ACCUMULATION, DECREASED HEPATOCYTE BALLOONING, AND IMPROVED STEATOSIS SCORES. HEPATIC HCOX-2 OVEREXPRESSION ENHANCED AKT INSULIN SIGNALING AND INCREASED FATTY ACID SYNTHESIS IN BOTH RCD AND HF+ETH DIET GROUPS. THE ANTI-LIPOGENIC EFFECT OF HCOX-2 TG IN THE HF+ETH DIET ANIMALS WAS MEDIATED BY INCREASING LIPID DISPOSAL THROUGH ENHANCED BETA-OXIDATION VIA ELEVATIONS IN THE EXPRESSION OF PPARALPHA AND PPARGAMMA, AND INCREASED HEPATIC AUTOPHAGY AS ASSESSED BY THE RATIO OF AUTOPHAGY MARKERS LC3 II/I IN HEPATIC TISSUE. VARIOUS PROTEIN ACETYLATION PATHWAY COMPONENTS, INCLUDING HAT, HDAC1, SIRT1, AND SNAIL1, WERE MODULATED IN HCOX-2 TG MICE IN EITHER RCD OR HF+ETH DIET. CONCLUSIONS: HEPATIC HUMAN COX-2 EXPRESSION PROTECTED MICE FROM THE METABOLIC DISORDER AND LIVER INJURY INDUCED BY A HIGH FAT AND ETHANOL DIET BY ENHANCING HEPATIC LIPID EXPENDITURE. EPIGENETIC REPROGRAMMING OF DIVERSE METABOLIC GENES MIGHT BE INVOLVED IN THE ANTI-LIPOGENIC EFFECT OF COX-2. 2021 12 3941 22 LNCRNA DRAIR IS DOWNREGULATED IN DIABETIC MONOCYTES AND MODULATES THE INFLAMMATORY PHENOTYPE VIA EPIGENETIC MECHANISMS. LONG NONCODING RNAS (LNCRNAS) ARE INCREASINGLY IMPLICATED IN THE PATHOLOGY OF DIABETIC COMPLICATIONS. HERE, WE EXAMINED THE ROLE OF LNCRNAS IN MONOCYTE DYSFUNCTION AND INFLAMMATION ASSOCIATED WITH HUMAN TYPE 2 DIABETES MELLITUS (T2D). RNA SEQUENCING ANALYSIS OF CD14+ MONOCYTES FROM PATIENTS WITH T2D VERSUS HEALTHY CONTROLS REVEALED DOWNREGULATION OF ANTIINFLAMMATORY AND ANTIPROLIFERATIVE GENES, ALONG WITH SEVERAL LNCRNAS, INCLUDING A POTENTIALLY NOVEL DIVERGENT LNCRNA DIABETES REGULATED ANTIINFLAMMATORY RNA (DRAIR) AND ITS NEARBY GENE CPEB2. HIGH GLUCOSE AND PALMITIC ACID DOWNREGULATED DRAIR IN CULTURED CD14+ MONOCYTES, WHEREAS ANTIINFLAMMATORY CYTOKINES AND MONOCYTE-TO-MACROPHAGE DIFFERENTIATION UPREGULATED DRAIR VIA KLF4 TRANSCRIPTION FACTOR. DRAIR OVEREXPRESSION INCREASED ANTIINFLAMMATORY AND MACROPHAGE DIFFERENTIATION GENES BUT INHIBITED PROINFLAMMATORY GENES. CONVERSELY, DRAIR KNOCKDOWN ATTENUATED ANTIINFLAMMATORY GENES, PROMOTED INFLAMMATORY RESPONSES, AND INHIBITED PHAGOCYTOSIS. DRAIR REGULATED TARGET GENE EXPRESSION THROUGH INTERACTION WITH CHROMATIN, AS WELL AS INHIBITION OF THE REPRESSIVE EPIGENETIC MARK H3K9ME2 AND ITS CORRESPONDING METHYLTRANSFERASE G9A. MOUSE ORTHOLOGOUS DRAIR AND CPEB2 WERE ALSO DOWNREGULATED IN PERITONEAL MACROPHAGES FROM T2D DB/DB MICE, AND DRAIR KNOCKDOWN IN NONDIABETIC MICE ENHANCED PROINFLAMMATORY GENES IN MACROPHAGES. THUS, DRAIR MODULATES THE INFLAMMATORY PHENOTYPE OF MONOCYTES/MACROPHAGES VIA EPIGENETIC MECHANISMS, AND ITS DOWNREGULATION IN T2D MAY PROMOTE CHRONIC INFLAMMATION. AUGMENTATION OF ENDOGENOUS LNCRNAS LIKE DRAIR COULD SERVE AS NOVEL ANTIINFLAMMATORY THERAPIES FOR DIABETIC COMPLICATIONS. 2021 13 2372 20 EPIGENETIC REGULATION OF THE IL-13-INDUCED HUMAN EOTAXIN-3 GENE BY CREB-BINDING PROTEIN-MEDIATED HISTONE 3 ACETYLATION. THE ETIOLOGY OF A VARIETY OF CHRONIC INFLAMMATORY DISORDERS HAS BEEN ATTRIBUTED TO THE INTERACTION OF GENETIC AND ENVIRONMENTAL FACTORS. HEREIN, WE IDENTIFIED A LINK BETWEEN EPIGENETIC REGULATION AND IL-13-DRIVEN EOTAXIN-3 IN THE PATHOGENESIS OF CHRONIC ALLERGIC INFLAMMATION. WE FIRST DEMONSTRATED THAT THE CAMP-RESPONSIVE ELEMENT (CRE) SITE IN THE EOTAXIN-3 PROMOTER AFFECTS IL-13-INDUCED EOTAXIN-3 PROMOTER ACTIVITY. FURTHERMORE, THE CRE-BINDING PROTEIN-BINDING PROTEIN (CBP), A HISTONE ACETYLTRANSFERASE, INDUCED BASE-LINE AND IL-13-INDUCED EOTAXIN-3 PROMOTER ACTIVITY. ADDITIONALLY, IL-13 TREATMENT PROMOTED GLOBAL HISTONE 3 ACETYLATION AS WELL AS THE FORMATION OF A COMPLEX CONTAINING CBP AND STAT6 AND THE SUBSEQUENT ACETYLATION OF HISTONE 3 AT THE EOTAXIN-3 PROMOTER. CBP GENE SILENCING DECREASED IL-13-INDUCED TRANSCRIPTION OF EOTAXIN-3. CONVERSELY, INHIBITION OF HISTONE DEACETYLATION INCREASED IL-13-INDUCED EOTAXIN-3 PRODUCTION. CLINICAL STUDIES DEMONSTRATED MARKEDLY INCREASED GLOBAL ACETYLATION OF HISTONE 3 IN THE INFLAMED TISSUE OF PATIENTS WITH ALLERGIC INFLAMMATION. COLLECTIVELY, THESE RESULTS IDENTIFY AN EPIGENETIC MECHANISM INVOLVING CBP AND CHROMATIN REMODELING IN REGULATING IL-13-INDUCED CHEMOKINE TRANSCRIPTION. 2011 14 3153 33 GLUCOSE-INDUCED EXPRESSION OF THE HOMEOTIC TRANSCRIPTION FACTOR PREP1 IS ASSOCIATED WITH HISTONE POST-TRANSLATIONAL MODIFICATIONS IN SKELETAL MUSCLE. AIMS/HYPOTHESIS: CHRONIC HYPERGLYCAEMIA WORSENS INSULIN RESISTANCE IN INDIVIDUALS WITH TYPE 2 DIABETES. WHETHER THIS EFFECT IS CONTRIBUTED BY EPIGENETIC DYSREGULATION AND WHICH GENES ARE INVOLVED REMAIN UNCLEAR. PREP1 (ALSO KNOWN AS PKNOX1) IS A GENE EXERTING MAJOR EFFECTS ON THE SENSITIVITY OF THE GLUCOSE TRANSPORT MACHINERY TO INSULIN. HERE, WE SHOW THAT DYSREGULATION OF PREP1 EXPRESSION BY HIGH GLUCOSE LEVELS IS ASSOCIATED WITH HISTONE MODIFICATIONS AT ITS 5' REGULATORY REGION. METHODS: WE USED MOUSE AND CELL MODELS TO INVESTIGATE PREP1 TRANSCRIPTIONAL REGULATION BY GLUCOSE. RESULTS: DIFFERENTIATED L6 SKELETAL MUSCLE CELLS WERE GROWN IN THE PRESENCE OF EITHER 5.5 OR 25 MMOL/L GLUCOSE (NORMAL [NG] AND HIGH GLUCOSE [HG], RESPECTIVELY). THE HG EXPOSURE INCREASED NUCLEAR FACTOR KAPPA LIGHT CHAIN ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) P65 BINDING AND RECRUITMENT OF THE SU(VAR)3-9, ENHANCER-OF-ZESTE, TRITHORAX DOMAIN-CONTAINING LYSINE METHYLTRANSFERASE 7 (SET7) HISTONE METHYLTRANSFERASE AND P300 ACETYLTRANSFERASE TO THE 5' REGION OF PREP1, LEADING TO ENHANCED TRANSCRIPTION. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION ASSAYS REVEALED CONCOMITANTLY INCREASED HISTONE H3 MONO- AND DIMETHYLATION AND ACETYLATION AT LYS4 AND LYS9/14, RESPECTIVELY. SKELETAL MUSCLE TISSUE FROM STREPTOZOTOCIN-TREATED DIABETIC MICE ALSO SHOWED PREP1 OVEREXPRESSION ACCOMPANIED BY SIMILARLY INCREASED RECRUITMENT OF NF-KAPPAB P65 AND HISTONE MODIFICATIONS AT THE 5' REGION OF PREP1. IN THESE SAME MICE, AS WELL AS IN PREP1-OVEREXPRESSING L6 CELLS, PREP1-INDUCED RECRUITMENT OF THE REPRESSOR COMPLEX MYOCYTE ENHANCER FACTOR 2 (MEF2)/HISTONE DEACETYLASE 5 (HDAC5) AT THE GLUT4 PROMOTER WAS ALSO INCREASED, LEADING TO REDUCED GLUT4 EXPRESSION. CONCLUSIONS/INTERPRETATION: THESE STUDIES INDICATE THAT HG EXPOSURE INDUCES NF-KAPPAB RECRUITMENT AND HISTONE MODIFICATION AT THE PREP1 5' REGION, THEREBY ENHANCING THE TRANSCRIPTION OF PREP1 AND REPRESSING THAT OF GLUT4. HISTONE CHANGES AT THE PREP1 GENE MAY CONTRIBUTE TO INSULIN RESISTANCE IN INDIVIDUALS WITH TYPE 2 DIABETES. 2016 15 2640 22 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS. 2021 16 3239 27 HEPATIC INACTIVATION OF THE TYPE 2 DEIODINASE CONFERS RESISTANCE TO ALCOHOLIC LIVER STEATOSIS. BACKGROUND: A MOUSE WITH HEPATOCYTE-SPECIFIC DEIODINASE TYPE II INACTIVATION (ALB-D2KO) IS RESISTANT TO DIET-INDUCED OBESITY, HEPATIC STEATOSIS, AND HYPERTRIGLYCERIDEMIA DUE TO PERINATAL EPIGENETIC MODIFICATIONS IN THE LIVER. THIS PHENOTYPE IS LINKED TO LOW LEVELS OF ZFP125, A HEPATIC TRANSCRIPTIONAL REPRESSOR THAT PROMOTES LIVER STEATOSIS BY INHIBITING GENES INVOLVED IN PACKAGING AND SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN. METHODS: HERE, WE USED CHRONIC AND BINGE ETHANOL (ETOH) IN MICE TO CAUSE LIVER STEATOSIS. RESULTS: THE ETOH TREATMENT CAUSES A 2.3-FOLD INCREASE IN HEPATIC TRIGLYCERIDE CONTENT; ZFP125 LEVELS WERE APPROXIMATELY 50% HIGHER IN THESE ANIMALS. IN CONTRAST, ALB-D2KO MICE DID NOT DEVELOP ETOH-INDUCED LIVER STEATOSIS. THEY ALSO FAILED TO ELEVATE ZFP125 TO THE SAME LEVELS, DESPITE BEING ON THE ETOH-CONTAINING DIET FOR THE SAME PERIOD OF TIME. THEIR PHENOTYPE WAS ASSOCIATED WITH 1.3- TO 2.9-FOLD UP-REGULATION OF HEPATIC GENES INVOLVED IN LIPID TRANSPORT AND EXPORT THAT ARE NORMALLY REPRESSED BY ZFP125, THAT IS, MTTP, ABCA1, LDLR, APOC1, APOC3, APOE, APOH, AND AZGP1. FURTHERMORE, GENES INVOLVED IN THE ETOH METABOLIC PATHWAY, THAT IS, ALDH2 AND ACSS2, WERE ALSO 1.6- TO 3.1-FOLD UP-REGULATED IN ALB-D2KO ETOH MICE COMPARED WITH CONTROL ANIMALS KEPT ON ETOH. CONCLUSIONS: ETOH CONSUMPTION ELEVATES EXPRESSION OF ZFP125. ALB-D2KO ANIMALS, WHICH HAVE LOWER LEVELS OF ZFP125, ARE MUCH LESS SUSCEPTIBLE TO ETOH-INDUCED LIVER STEATOSIS. 2019 17 2263 26 EPIGENETIC PROGRAMMING AT THE MOGAT1 LOCUS MAY LINK NEONATAL OVERNUTRITION WITH LONG-TERM HEPATIC STEATOSIS AND INSULIN RESISTANCE. POSTNATAL OVERFEEDING INCREASES THE RISK OF CHRONIC DISEASES LATER IN LIFE, INCLUDING OBESITY, INSULIN RESISTANCE, HEPATIC STEATOSIS, AND TYPE 2 DIABETES. EPIGENETIC MECHANISMS MIGHT UNDERLIE THE LONG-LASTING EFFECTS ASSOCIATED WITH EARLY NUTRITION. HERE WE AIMED TO EXPLORE THE MOLECULAR PATHWAYS INVOLVED IN EARLY DEVELOPMENT OF INSULIN RESISTANCE AND HEPATIC STEATOSIS, AND WE EXAMINED THE POTENTIAL CONTRIBUTION OF DNA METHYLATION AND HISTONE MODIFICATIONS TO LONG-TERM PROGRAMMING OF METABOLIC DISEASE. WE USED A WELL-CHARACTERIZED MOUSE MODEL OF NEONATAL OVERFEEDING AND EARLY ADIPOSITY BY LITTER SIZE REDUCTION. NEONATAL OVERFEEDING LED TO HEPATIC INSULIN RESISTANCE VERY EARLY IN LIFE THAT PERSISTED THROUGHOUT ADULTHOOD DESPITE NORMALIZING FOOD INTAKE. UP-REGULATION OF MONOACYLGLYCEROL O-ACYLTRANSFERASE ( MOGAT) 1 CONCEIVABLY MEDIATES HEPATIC STEATOSIS AND INSULIN RESISTANCE THROUGH INCREASING INTRACELLULAR DIACYLGLYCEROL CONTENT. EARLY AND SUSTAINED DEREGULATION OF MOGAT1 WAS ASSOCIATED WITH A COMBINATION OF HISTONE MODIFICATIONS THAT MIGHT FAVOR MOGAT1 EXPRESSION. IN SUM, POSTNATAL OVERFEEDING CAUSES EXTREMELY RAPID DERANGEMENTS OF HEPATIC INSULIN SENSITIVITY THAT REMAIN RELATIVELY STABLE UNTIL ADULTHOOD. EPIGENETIC MECHANISMS, PARTICULARLY HISTONE MODIFICATIONS, COULD CONTRIBUTE TO SUCH LONG-LASTING EFFECTS. OUR DATA SUGGEST THAT TARGETING HEPATIC MONOACYLGLYCEROL ACYLTRANSFERASE ACTIVITY DURING EARLY LIFE MIGHT PROVIDE A NOVEL STRATEGY TO IMPROVE HEPATIC INSULIN SENSITIVITY AND PREVENT LATE-ONSET INSULIN RESISTANCE AND FATTY LIVER DISEASE.-RAMON-KRAUEL, M., PENTINAT, T., BLOKS, V. W., CEBRIA, J., RIBO, S., PEREZ-WIENESE, R., VILA, M., PALACIOS-MARIN, I., FERNANDEZ-PEREZ, A., VALLEJO, M., TELLEZ, N., RODRIGUEZ, M. A., YANES, O., LERIN, C., DIAZ, R., PLOSCH, T., TIETGE, U. J. F., JIMENEZ-CHILLARON, J. C. EPIGENETIC PROGRAMMING AT THE MOGAT1 LOCUS MAY LINK NEONATAL OVERNUTRITION WITH LONG-TERM HEPATIC STEATOSIS AND INSULIN RESISTANCE. 2018 18 2809 30 FGF1 AMELIORATES OBESITY-ASSOCIATED HEPATIC STEATOSIS BY REVERSING IGFBP2 HYPERMETHYLATION. OBESITY IS A MAJOR CONTRIBUTING FACTOR FOR METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD). FIBROBLAST GROWTH FACTOR (FGF) 1 IS THE FIRST PARACRINE FGF FAMILY MEMBER IDENTIFIED TO EXHIBIT PROMISING METABOLIC REGULATORY PROPERTIES CAPABLE OF CONFERRING GLUCOSE-LOWERING AND INSULIN-SENSITIZING EFFECT. THIS STUDY EXPLORES THE ROLE AND MOLECULAR UNDERPINNINGS OF FGF1 IN OBESITY-ASSOCIATED HEPATIC STEATOSIS. IN A MOUSE HIGH-FAT DIET (HFD)-INDUCED MAFLD MODEL, CHRONIC TREATMENT WITH RECOMBINANT FGF1(RFGF1) WAS FOUND TO EFFECTIVELY REDUCE THE SEVERITY OF INSULIN RESISTANCE, HYPERLIPIDEMIA, AND INFLAMMATION. FGF1 TREATMENT DECREASED LIPID ACCUMULATION IN THE MOUSE LIVER AND PALMITIC ACID-TREATED AML12 CELLS. THESE EFFECTS WERE ASSOCIATED WITH DECREASED MATURE FORM SREBF1 EXPRESSION AND ITS TARGET GENES FASN AND SCD1. INTERESTINGLY, WE UNCOVERED THAT RFGF1 SIGNIFICANTLY INDUCED IGFBP2 EXPRESSION AT BOTH MRNA AND PROTEIN LEVELS IN HFD-FED MOUSE LIVERS AND CULTURED HEPATOCYTES TREATED WITH PALMITIC ACID. ADENO-ASSOCIATED VIRUS-MEDIATED IGFBP2 SUPPRESSION SIGNIFICANTLY DIMINISHED THE THERAPEUTIC BENEFIT OF RFGF1 ON MAFLD-ASSOCIATED PHENOTYPES, INDICATING THAT IGFBP2 PLAYS A CRUCIAL ROLE IN THE FGF1-MEDIATED REDUCTION OF HEPATIC STEATOSIS. FURTHER ANALYSIS REVEALED THAT RFGF1 TREATMENT REDUCES THE RECRUITMENT OF DNA METHYLTRANSFERASE 3 ALPHA TO THE IGFBP2 GENOMIC LOCUS, LEADING TO DECREASED IGFBP2 GENE METHYLATION AND INCREASED MRNA AND PROTEIN EXPRESSION. COLLECTIVELY, OUR FINDINGS REVEAL FGF1 MODULATION OF LIPID METABOLISM VIA EPIGENETIC REGULATION OF IGFBP2 EXPRESSION, AND UNRAVEL THE THERAPEUTIC POTENTIAL OF THE FGF1-IGFBP2 AXIS IN METABOLIC DISEASES ASSOCIATED WITH OBESITY. 2023 19 875 21 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 20 2397 22 EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES PROMOTES POLARIZATION AND INFLAMMATION IN MUCO-OBSTRUCTIVE LUNG DISEASE. LUNG DISEASES, SUCH AS CYSTIC FIBROSIS AND COPD, ARE CHARACTERIZED BY MUCUS OBSTRUCTION AND CHRONIC AIRWAY INFLAMMATION, BUT THEIR MECHANISTIC LINK REMAINS POORLY UNDERSTOOD. HERE, WE FOCUS ON THE FUNCTION OF THE MUCOSTATIC AIRWAY MICROENVIRONMENT ON EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES (AM) AND RESULTING TRANSCRIPTOMIC AND PHENOTYPICAL CHANGES. USING A MOUSE MODEL OF MUCO-OBSTRUCTIVE LUNG DISEASE (SCNN1B-TRANSGENIC), WE IDENTIFY EPIGENETICALLY CONTROLLED, DIFFERENTIALLY REGULATED PATHWAYS AND TRANSCRIPTION FACTORS INVOLVED IN INFLAMMATORY RESPONSES AND MACROPHAGE POLARIZATION. FUNCTIONALLY, AMS FROM SCNN1B-TRANSGENIC MICE HAVE REDUCED EFFEROCYTOSIS AND PHAGOCYTOSIS, AND EXCESSIVE INFLAMMATORY RESPONSES UPON LIPOPOLYSACCHARIDE CHALLENGE, MEDIATED THROUGH ENHANCED IRF1 FUNCTION AND EXPRESSION. EX VIVO STIMULATION OF WILD-TYPE AMS WITH NATIVE MUCUS IMPAIRS EFFEROCYTOSIS AND PHAGOCYTOSIS CAPACITIES. IN ADDITION, MUCUS INDUCES GENE EXPRESSION CHANGES, COMPARABLE WITH THOSE OBSERVED IN AMS FROM SCNN1B-TRANSGENIC MICE. OUR DATA SHOW THAT MUCOSTASIS INDUCES EPIGENETIC REPROGRAMMING OF AMS, LEADING TO CHANGES FAVORING TISSUE DAMAGE AND DISEASE PROGRESSION. TARGETING THESE ALTERED AMS MAY SUPPORT THERAPEUTIC APPROACHES IN PATIENTS WITH MUCO-OBSTRUCTIVE LUNG DISEASES. 2021