1 6277 167 THE PATHOGENIC ROLE OF PERSISTENT MILK SIGNALING IN MTORC1- AND MILK-MICRORNA-DRIVEN TYPE 2 DIABETES MELLITUS. MILK, THE SECRETORY PRODUCT OF THE LACTATION GENOME, PROMOTES GROWTH OF THE NEWBORN MAMMAL. MILK DELIVERS INSULINOTROPIC AMINO ACIDS, THUS MAINTAINS A MOLECULAR CROSSTALK WITH THE PANCREATIC BETA-CELL OF THE MILK RECIPIENT. HOMEOSTASIS OF BETA-CELLS AND INSULIN PRODUCTION DEPEND ON THE APPROPRIATE MAGNITUDE OF MTORC1 SIGNALING. MTORC1 IS ACTIVATED BY BRANCHED-CHAIN AMINO ACIDS (BCAAS), GLUTAMINE, AND PALMITIC ACID, ABUNDANT NUTRIENT SIGNALS OF COW S MILK. FURTHERMORE, MILK DELIVERS BIOACTIVE EXOSOMAL MICRORNAS. AFTER MILK CONSUMPTION, BOVINE MICRORNA-29B, A MEMBER OF THE DIABETOGENIC MICRORNA-29- FAMILY, REACHES THE SYSTEMIC CIRCULATION AND THE CELLS OF THE MILK CONSUMER. MICRORNA-29B DOWNREGULATES BRANCHEDCHAIN ALPHA-KETOACID DEHYDROGENASE, A POTENTIAL EXPLANATION FOR INCREASED BCAA SERUM LEVELS, THE METABOLIC SIGNATURE OF INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS (T2DM). IN NON-OBESE DIABETIC MICE, MICRORNA-29B DOWNREGULATES THE ANTIAPOPTOTIC PROTEIN MCL-1, WHICH LEADS TO EARLY BETA-CELL DEATH. IN ALL MAMMALS EXCEPT NEOLITHIC HUMANS, MILK-DRIVEN MTORC1 SIGNALING IS PHYSIOLOGICALLY RESTRICTED TO THE POSTNATAL PERIOD. IN CONTRAST, CHRONIC HYPERACTIVATED MTORC1 SIGNALING HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF AGE-RELATED DISEASES OF CIVILIZATION INCLUDING T2DM. NOTABLY, CHRONIC HYPERACTIVATION OF MTORC1 ENHANCES ENDOPLASMIC RETICULUM STRESS THAT PROMOTES APOPTOSIS. IN FACT, HYPERACTIVATED BETA-CELL MTORC1 SIGNALING INDUCED EARLY BETA-CELL APOPTOSIS IN A MOUSE MODEL. THE EPIC-INTERACT STUDY DEMONSTRATED AN ASSOCIATION BETWEEN MILK CONSUMPTION AND T2DM IN FRANCE, ITALY, UNITED KINGDOM, GERMANY, AND SWEDEN. IN CONTRAST, FERMENTED MILK PRODUCTS AND CHEESE EXHIBIT AN INVERSE CORRELATION. SINCE THE EARLY 1950 S, REFRIGERATION TECHNOLOGY ALLOWED WIDESPREAD CONSUMPTION OF FRESH PASTEURIZED MILK, WHICH FACILITATES DAILY INTAKE OF BIOACTIVE BOVINE MICRORNAS. PERSISTENT UPTAKE OF COW S MILK-DERIVED MICRORNAS APPARENTLY TRANSFERS AN OVERLOOKED EPIGENETIC DIABETOGENIC PROGRAM THAT SHOULD NOT REACH THE HUMAN FOOD CHAIN. 2015 2 2701 20 EXCESSIVE BRANCHED-CHAIN AMINO ACID ACCUMULATION RESTRICTS MESENCHYMAL STEM CELL-BASED THERAPY EFFICACY IN MYOCARDIAL INFARCTION. MESENCHYMAL STEM CELLS (MSCS) DELIVERED INTO THE POST-ISCHEMIC HEART MILIEU HAVE A LOW SURVIVAL AND RETENTION RATE, THUS RESTRICTING THE CARDIOREPARATIVE EFFICACY OF MSC-BASED THERAPY. CHRONIC ISCHEMIA RESULTS IN METABOLIC REPROGRAMMING IN THE HEART, BUT LITTLE IS KNOWN ABOUT HOW THESE METABOLIC CHANGES INFLUENCE IMPLANTED MSCS. HERE, WE FOUND THAT EXCESSIVE BRANCHED-CHAIN AMINO ACID (BCAA) ACCUMULATION, A METABOLIC SIGNATURE SEEN IN THE POST-ISCHEMIC HEART, WAS DISADVANTAGEOUS TO THE RETENTION AND CARDIOPROTECTION OF INTRAMYOCARDIALLY INJECTED MSCS. DISCOVERY-DRIVEN EXPERIMENTS REVEALED THAT BCAA AT PATHOLOGICAL LEVELS SENSITIZED MSCS TO STRESS-INDUCED CELL DEATH AND PREMATURE SENESCENCE VIA ACCELERATING THE LOSS OF HISTONE 3 LYSINE 9 TRIMETHYLATION (H3K9ME3). A NOVEL MTORC1/DUX4/KDM4E AXIS WAS IDENTIFIED AS THE CAUSE OF BCAA-INDUCED H3K9ME3 LOSS AND ADVERSE PHENOTYPE ACQUISITION. ENHANCING BCAA CATABOLIC CAPABILITY IN MSCS VIA GENETIC/PHARMACOLOGICAL APPROACHES GREATLY IMPROVED THEIR ADAPTATION TO THE HIGH BCAA MILIEU AND STRENGTHENED THEIR CARDIOPROTECTIVE EFFICACY. WE CONCLUDE THAT ABERRANT BCAA ACCUMULATION IS DETRIMENTAL TO IMPLANTED MSCS VIA A PREVIOUSLY UNKNOWN METABOLITE-SIGNALING-EPIGENETIC MECHANISM, EMPHASIZING THAT THE METABOLIC CHANGES OF THE POST-ISCHEMIC HEART CRUCIALLY INFLUENCE THE FATE OF IMPLANTED MSCS AND THEIR THERAPEUTIC BENEFITS. 2022 3 4505 26 MOUSE MODELS AND THE GENETICS OF DIABETES: IS THERE EVIDENCE FOR GENETIC OVERLAP BETWEEN TYPE 1 AND TYPE 2 DIABETES? IN HUMANS, BOTH TYPE 1 AND TYPE 2 DIABETES EXEMPLIFY GENETICALLY HETEROGENEOUS COMPLEX DISEASES IN WHICH EPIGENETIC FACTORS CONTRIBUTE TO UNDERLYING GENETIC SUSCEPTIBILITY. EXTENDED HUMAN PEDIGREES OFTEN SHOW INHERITANCE OF BOTH DIABETES TYPES. A COMMON PATHOPHYSIOLOGICAL DENOMINATOR IN BOTH DISEASE FORMS IS PANCREATIC BETA-CELL EXPOSURE TO PROINFLAMMATORY CYTOKINES. HENCE, IT IS INTUITIVE THAT SYSTEMICALLY EXPRESSED GENES REGULATING BETA-CELL ABILITY TO WITHSTAND CHRONIC DIABETOGENIC STRESS MAY REPRESENT A COMPONENT OF SHARED SUSCEPTIBILITY TO BOTH MAJOR DISEASE FORMS. IN THIS REVIEW, THE AUTHORS ASSEMBLE EVIDENCE FROM GENETIC EXPERIMENTS USING ANIMAL MODELS DEVELOPING CLEARLY DISTINCT DIABETES SYNDROMES TO INQUIRE WHETHER SOME DEGREE OF OVERLAP IN GENES CONTRIBUTING SUSCEPTIBILITY CAN BE DEMONSTRATED. THE CONCLUSION IS THAT ALTHOUGH OVERLAP EXISTS IN THE PATHOPHYSIOLOGICAL INSULTS LEADING TO BETA-CELL DESTRUCTION IN THE CURRENTLY STUDIED RODENT MODELS, THE GENETIC BASES SEEM QUITE DISTINCT. 2005 4 3801 33 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 5 5281 32 PROMOTION AND SELECTION BY SERUM GROWTH FACTORS DRIVE FIELD CANCERIZATION, WHICH IS ANTICIPATED IN VIVO BY TYPE 2 DIABETES AND OBESITY. INDIVIDUALS SUFFERING FROM TYPE 2 DIABETES OR OBESITY EXHIBIT A SIGNIFICANT INCREASE IN THE INCIDENCE OF VARIOUS TYPES OF CANCER. IT IS GENERALLY ACCEPTED THAT THOSE CONDITIONS ARISE FROM OVERNUTRITION AND A SEDENTARY LIFESTYLE, WHICH LEAD TO INSULIN RESISTANCE CHARACTERIZED BY OVERPRODUCTION OF INSULIN ACTING AS A GROWTH FACTOR. THERE IS A CONSENSUS BASED LARGELY ON EPIDEMIOLOGICAL DATA THAT CHRONIC OVERPRODUCTION OF INSULIN IS RESPONSIBLE FOR THE INCREASED INCIDENCE OF CANCER. A MODEL SYSTEM IN CULTURE OF NIH 3T3 CELLS INDUCES THE COLLECTIVE EFFECTS OF SERUM GROWTH FACTORS ON PROGRESSION THROUGH THE STAGES OF FIELD CANCERIZATION. IT SHOWS THAT THE DRIVING FORCE OF PROGRESSION IS PROMOTION OF CELL GROWTH UNDER SELECTION AT HIGH CELL DENSITY, WITH NO REQUIREMENT FOR EXOGENOUS CARCINOGENIC AGENTS. THE EARLY EFFECT IS GRADUAL SELECTION AMONG MANY PREEXISTING, LOW-PENETRANCE PRENEOPLASTIC MUTATIONS OR STABLE EPIGENETIC VARIANTS, FOLLOWED BY SPORADIC, HIGH-PENETRANCE TRANSFORMING VARIANTS, ALL DEPENDENT ON ENDOGENOUS PROCESSES. THE SIGNIFICANCE OF THE RESULTS FOR CANCER IN DIABETIC AND OBESE INDIVIDUALS IS THAT THE INITIAL STAGES OF THE PROCESS INVOLVE MULTIORGAN METABOLIC INTERACTIONS THAT PRODUCE A SYSTEMIC INSULIN RESISTANCE WITH CHRONIC OVERPRODUCTION OF INSULIN AND LOCALIZED FIELD CANCERIZATION. HYPOMAGNESEMIA IS PREVALENT IN THE FOREGOING METABALO/SYSTEMIC DISORDERS, AND MAY ALSO PROVIDE A SELECTIVE MICROENVIRONMENT FOR TUMOR DEVELOPMENT. 2013 6 1900 31 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 7 5614 34 SAFETY AND EFFICACY OF EPIGENETICALLY CONVERTED HUMAN FIBROBLASTS INTO INSULIN-SECRETING CELLS: A PRECLINICAL STUDY. TYPE 1 DIABETES MELLITUS (T1DM) IS A CHRONIC DISEASE THAT LEADS TO LOSS OF INSULIN SECRETING BETA-CELLS, CAUSING HIGH LEVELS OF BLOOD GLUCOSE. EXOGENOUS INSULIN ADMINISTRATION IS NOT SUFFICIENT TO MIMIC THE NORMAL FUNCTION OF BETA-CELLS AND, CONSEQUENTLY, DIABETES MELLITUS OFTEN PROGRESSES AND CAN LEAD TO MAJOR CHRONIC COMPLICATIONS AND MORBIDITY. THE PHYSIOLOGICAL CONTROL OF GLUCOSE LEVELS CAN ONLY BE RESTORED BY REPLACING THE BETA-CELL MASS.WE RECENTLY DEVELOPED A NEW STRATEGY THAT ALLOWS FOR EPIGENETIC CONVERSION OF DERMAL FIBROBLASTS INTO INSULIN-SECRETING CELLS (EPICC), USING A BRIEF EXPOSURE TO THE DEMETHYLATING AGENT 5-AZA-CYTIDINE (5-AZA-CR), FOLLOWED BY A PANCREATIC INDUCTION PROTOCOL. THIS METHOD HAS NOTABLE ADVANTAGES COMPARED TO THE ALTERNATIVE AVAILABLE PROCEDURES AND MAY REPRESENT A PROMISING TOOL FOR CLINICAL TRANSLATION AS A THERAPY FOR T1DM. HOWEVER, A THOUGHT EVALUATION OF ITS THERAPEUTIC SAFETY AND EFFICACY IS MANDATORY TO SUPPORT PRECLINICAL STUDIES BASED ON EPICC TREATMENT.WE HERE REPORT THE DATA OBTAINED USING HUMAN FIBROBLASTS ISOLATED FROM DIABETIC AND HEALTHY INDIVIDUALS, BELONGING THE TWO GENDERS. EPICC WERE INJECTED INTO 650 DIABETIC SEVERE COMBINED IMMUNODEFICIENCY (SCID) MICE AND DEMONSTRATED TO BE ABLE TO RESTORE AND MAINTAIN GLYCEMIC LEVELS WITHIN THE PHYSIOLOGICAL RANGE. CELLS HAD THE ABILITY TO SELF-REGULATE AND NOT TO CAUSE HYPOGLYCEMIA, WHEN TRANSPLANTED IN HEALTHY ANIMALS. EFFICACY TESTS SHOWED THAT EPICC SUCCESSFULLY RE-ESTABLISHED NORMOGLYCEMIA IN DIABETIC MICE, USING A DOSE RANGE THAT APPEARED CLINICALLY RELEVANT TO THE CONCENTRATION 0.6 X 10(6) EPICC. NECROPSY AND HISTOPATHOLOGICAL INVESTIGATIONS DEMONSTRATED THE ABSENCE OF MALIGNANT TRANSFORMATION AND CELL MIGRATION TO ORGANS AND LYMPH NODES.THE PRESENT PRECLINICAL STUDY DEMONSTRATES SAFETY AND EFFICACY OF HUMAN EPICC IN DIABETIC MICE AND SUPPORTS THE USE OF EPIGENETIC CONVERTED CELLS FOR REGENERATIVE MEDICINE OF DIABETES MELLITUS. 2018 8 4992 21 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 9 6022 29 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 10 702 36 BROWN RICE-SPECIFIC GAMMA-ORYZANOL AS A PROMISING PROPHYLACTIC AVENUE TO PROTECT AGAINST DIABETES MELLITUS AND OBESITY IN HUMANS. CHRONIC OVERCONSUMPTION OF ANIMAL FATS CAUSES A VARIETY OF HEALTH PROBLEMS, INCLUDING DIABETES MELLITUS AND OBESITY. UNDERLYING MOLECULAR MECHANISMS ENCOMPASS LEPTIN RESISTANCE, A DECREASE IN REWARDING EFFECTS OF PHYSICAL ACTIVITIES, XANTHINE OXIDASE-INDUCED OXIDATIVE STRESS IN VASCULATURE AND PERIPHERAL TISSUE, IMPAIRED ACTIVATION OF INCRETIN SIGNALING, DEVIATION IN FOOD PREFERENCE, AND DYSBIOSIS OF GUT MICROBIOTA. BASED ON OUR CLINICAL OBSERVATION THAT DAILY INTAKE OF BROWN RICE EFFECTIVELY AMELIORATES BODYWEIGHT GAIN, IMPAIRED GLUCOSE TOLERANCE/INSULIN RESISTANCE AND DEPENDENCE ON FATTY FOODS IN OBESE, PREDIABETES MEN, A LINE OF RESEARCH ON BROWN RICE (RICE BRAN)-DERIVED GAMMA-ORYZANOL IN MICE EXPERIMENTS, CULTURED CELLS AND HUMAN CLINICAL TRIALS IS UNDERWAY IN OUR LABORATORY. OUR WORKS IN MICE SHOWED THAT GAMMA-ORYZANOL, AN ESTER MIXTURE OF FERULIC ACID AND SEVERAL KINDS OF PHYTOSTEROLS, ACTS AS A MOLECULAR CHAPERONE, THEREBY ATTENUATING THE STRONG PREFERENCE FOR ANIMAL FATS THROUGH SUPPRESSION OF ENDOPLASMIC RETICULUM STRESS IN THE HYPOTHALAMUS. IN PANCREATIC ISLETS FROM BOTH HIGH-FAT DIET-INDUCED AND STREPTOZOTOCIN-INDUCED DIABETIC MICE, GAMMA-ORYZANOL AMELIORATES ENDOPLASMIC RETICULUM STRESS AND PROTECTS BETA-CELLS AGAINST APOPTOSIS. NOTICEABLY, GAMMA-ORYZANOL ALSO ACTS AS A POTENT INHIBITOR AGAINST DEOXYRIBONUCLEIC ACID METHYLTRANSFERASES IN THE BRAIN REWARD SYSTEM (STRIATUM) IN MICE, THEREBY ATTENUATING, AT LEAST PARTLY, THE PREFERENCE FOR A HIGH-FAT DIET THROUGH THE EPIGENETIC MODULATION OF STRIATAL DOPAMINE D2 RECEPTOR. BECAUSE DOPAMINE D2 RECEPTOR SIGNALING IN THE BRAIN REWARD SYSTEM IS CONSIDERABLY ATTENUATED IN OBESE HUMANS AND RODENTS, GAMMA-ORYZANOL MIGHT REPRESENT A UNIQUE PROPERTY TO AMELIORATE BOTH HEDONIC AND METABOLIC DYSREGULATION OF FEEDING BEHAVIOR, HIGHLIGHTING A PROMISING PROPHYLACTIC AVENUE TO PROTECT AGAINST METABOLIC DERANGEMENT. 2019 11 1841 31 EFFECTS OF SHORT CHAIN FATTY ACID PRODUCING BACTERIA ON EPIGENETIC REGULATION OF FFAR3 IN TYPE 2 DIABETES AND OBESITY. THE HUMAN GUT MICROBIOTA AND MICROBIAL INFLUENCES ON LIPID AND GLUCOSE METABOLISM, SATIETY, AND CHRONIC LOW-GRADE INFLAMMATION ARE KNOWN TO BE INVOLVED IN METABOLIC SYNDROME. FERMENTATION END PRODUCTS, ESPECIALLY SHORT CHAIN FATTY ACIDS, ARE BELIEVED TO ENGAGE THE EPIGENETIC REGULATION OF INFLAMMATORY REACTIONS VIA FFARS (FREE FATTY ACID RECEPTOR) AND OTHER SHORT CHAIN FATTY ACID RECEPTORS. WE STUDIED A POTENTIAL INTERACTION OF THE MICROBIOTA WITH EPIGENETIC REGULATION IN OBESE AND TYPE 2 DIABETES PATIENTS COMPARED TO A LEAN CONTROL GROUP OVER A FOUR MONTH INTERVENTION PERIOD. INTERVENTION COMPRISED A GLP-1 AGONIST (GLUCAGON-LIKE PEPTIDE 1) FOR TYPE 2 DIABETICS AND NUTRITIONAL COUNSELING FOR BOTH INTERVENTION GROUPS. MICROBIOTA WAS ANALYZED FOR ABUNDANCE, BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND FOR DIVERSITY BY POLYMERASE CHAIN REACTION AND 454 HIGH-THROUGHPUT SEQUENCING. EPIGENETIC METHYLATION OF THE PROMOTER REGION OF FFAR3 AND LINE1 (LONG INTERSPERSED NUCLEAR ELEMENT 1) WAS ANALYZED USING BISULFITE CONVERSION AND PYROSEQUENCING. THE DIVERSITY OF THE MICROBIOTA AS WELL AS THE ABUNDANCE OF FAECALIBACTERIUM PRAUSNITZII WERE SIGNIFICANTLY LOWER IN OBESE AND TYPE 2 DIABETIC PATIENTS COMPARED TO LEAN INDIVIDUALS. RESULTS FROM CLOSTRIDIUM CLUSTER IV AND CLOSTRIDIUM CLUSTER XIVA SHOWED A DECREASING TREND IN TYPE 2 DIABETICS IN COMPARISON TO THE BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND ACCORDING TO MELT CURVE ANALYSIS. DURING INTERVENTION NO SIGNIFICANT CHANGES WERE OBSERVED IN EITHER INTERVENTION GROUP. THE ANALYSIS OF FIVE CPGS IN THE PROMOTER REGION OF FFAR3 SHOWED A SIGNIFICANT LOWER METHYLATION IN OBESE AND TYPE 2 DIABETICS WITH AN INCREASE IN OBESE PATIENTS OVER THE INTERVENTION PERIOD. THESE RESULTS DISCLOSED A SIGNIFICANT CORRELATION BETWEEN A HIGHER BODY MASS INDEX AND LOWER METHYLATION OF FFAR3. LINE-1, A MARKER OF GLOBAL METHYLATION, INDICATED NO SIGNIFICANT DIFFERENCES BETWEEN THE THREE GROUPS OR THE TIME POINTS, ALTHOUGH METHYLATION OF TYPE 2 DIABETICS TENDED TO INCREASE OVER TIME. OUR RESULTS PROVIDE EVIDENCE THAT A DIFFERENT COMPOSITION OF GUT MICROBIOTA IN OBESITY AND TYPE 2 DIABETES AFFECT THE EPIGENETIC REGULATION OF GENES. INTERACTIONS BETWEEN THE MICROBIOTA AND EPIGENETIC REGULATION MAY INVOLVE NOT ONLY SHORT CHAIN FATTY ACIDS BINDING TO FFARS. THEREFORE DIETARY INTERVENTIONS INFLUENCING MICROBIAL COMPOSITION MAY BE CONSIDERED AS AN OPTION IN THE ENGAGEMENT AGAINST METABOLIC SYNDROME. 2014 12 599 30 BETA-CELL DIFFERENTIATION STATUS IN TYPE 2 DIABETES. TYPE 2 DIABETES (T2D) AFFECTS 415 MILLION PEOPLE WORLDWIDE AND IS CHARACTERIZED BY CHRONIC HYPERGLYCAEMIA AND INSULIN RESISTANCE, PROGRESSING TO INSUFFICIENT INSULIN PRODUCTION, AS A RESULT OF BETA-CELL FAILURE. OVER TIME, CHRONIC HYPERGLYCAEMIA CAN ULTIMATELY LEAD TO LOSS OF BETA-CELL FUNCTION, LEAVING PATIENTS INSULIN-DEPENDENT. UNTIL RECENTLY THE LOSS OF BETA-CELL MASS SEEN IN T2D WAS CONSIDERED TO BE THE RESULT OF INCREASED RATES OF APOPTOSIS; HOWEVER, IT HAS BEEN PROPOSED THAT APOPTOSIS ALONE CANNOT ACCOUNT FOR THE EXTENT OF BETA-CELL MASS LOSS SEEN IN THE DISEASE, AND THAT A LOSS OF FUNCTION MAY ALSO OCCUR AS A RESULT OF CHANGES IN BETA-CELL DIFFERENTIATION STATUS. IN THE PRESENT REVIEW, WE CONSIDER CURRENT KNOWLEDGE OF DETERMINANTS OF BETA-CELL FATE IN THE CONTEXT OF UNDERSTANDING ITS RELEVANCE TO DISEASE PROCESS IN T2D, AND ALSO THE IMPACT OF A DIABETOGENIC ENVIRONMENT (HYPERGLYCAEMIA, HYPOXIA, INFLAMMATION AND DYSLIPIDAEMIA) ON THE EXPRESSION OF GENES INVOLVED IN MAINTENANCE OF BETA-CELL IDENTITY. WE DESCRIBE CURRENT KNOWLEDGE OF THE IMPACT OF THE DIABETIC MICROENVIRONMENT ON GENE REGULATORY PROCESSES SUCH ALTERNATIVE SPLICING, THE EXPRESSION OF DISALLOWED GENES AND EPIGENETIC MODIFICATIONS. ELUCIDATING THE MOLECULAR MECHANISMS THAT UNDERPIN CHANGES TO BETA-CELL DIFFERENTIATION STATUS AND THE CONCOMITANT BETA-CELL FAILURE OFFERS POTENTIAL TREATMENT TARGETS FOR THE FUTURE MANAGEMENT OF PATIENTS WITH T2D. 2016 13 4263 30 MICRO(RNA) MANAGEMENT AND MISMANAGEMENT OF THE ISLET. PANCREATIC BETA-CELLS LOCATED WITHIN THE ISLETS OF LANGERHANS PLAY A CENTRAL ROLE IN METABOLIC CONTROL. THE MAIN FUNCTION OF THESE CELLS IS TO PRODUCE AND SECRETE INSULIN IN RESPONSE TO A RISE IN CIRCULATING LEVELS OF GLUCOSE AND OTHER NUTRIENTS. THE RELEASE OF INSUFFICIENT INSULIN TO COVER THE ORGANISM NEEDS RESULTS IN CHRONIC HYPERGLYCEMIA AND DIABETES DEVELOPMENT. BETA-CELLS INSURE A HIGHLY SPECIALIZED TASK AND TO EFFICIENTLY ACCOMPLISH THEIR FUNCTION THEY NEED TO EXPRESS A SPECIFIC SET OF GENES. MICRORNAS (MIRNAS) ARE SMALL NONCODING RNAS AND KEY REGULATORS OF GENE EXPRESSION. INDEED, BY PARTIALLY PAIRING TO SPECIFIC SEQUENCES IN THE 3' UNTRANSLATED REGIONS OF TARGET MRNAS, EACH OF THEM CAN CONTROL THE TRANSLATION OF HUNDREDS OF TRANSCRIPTS. IN THIS REVIEW, WE FOCUS ON FEW KEY MIRNAS CONTROLLING ISLET FUNCTION AND DISCUSS: THEIR DIFFERENTIAL EXPRESSION IN TYPE 2 DIABETES (T2D), THEIR REGULATION BY GENETIC AND ENVIRONMENTAL FACTORS, AND THEIR THERAPEUTIC POTENTIAL. GENETIC AND EPIGENETIC CHANGES OR PROLONGED EXPOSURE TO HYPERGLYCEMIA AND/OR HYPERLIPIDEMIA CAN AFFECT THE BETA-CELL MIRNA EXPRESSION PROFILE, RESULTING IN IMPAIRED BETA-CELL FUNCTION AND SURVIVAL LEADING TO THE DEVELOPMENT OF T2D. EXPERIMENTAL APPROACHES PERMITTING TO CORRECT THE LEVEL OF MISEXPRESSED MIRNAS HAVE BEEN SHOWN TO PREVENT OR TREAT T2D IN ANIMAL MODELS, SUGGESTING THAT THESE SMALL RNAS MAY BECOME INTERESTING THERAPEUTIC TARGETS. HOWEVER, TRANSLATION OF THESE EXPERIMENTAL FINDINGS TO THE CLINICS WILL NECESSITATE THE DEVELOPMENT OF INNOVATIVE STRATEGIES ALLOWING SAFE AND SPECIFIC DELIVERY OF COMPOUNDS MODULATING THE LEVEL OF THE RELEVANT MIRNAS TO THE BETA-CELLS. 2020 14 1913 35 ENVIRONMENTAL AND GENETIC CONTRIBUTIONS TO DIABETES. DIABETES MELLITUS (DM) IS A HETEROGENEOUS GROUP OF DISORDERS CHARACTERIZED BY PERSISTENT HYPERGLYCEMIA. ITS TWO MOST COMMON FORMS ARE TYPE 1 DIABETES (T1D) AND TYPE 2 DIABETES (T2D), FOR WHICH GENETIC AND ENVIRONMENTAL RISK FACTORS ACT IN SYNERGY. BECAUSE IT OCCURS IN CHILDREN AND INVOLVES INFECTIOUS, AUTOIMMUNE OR TOXIC DESTRUCTION OF THE INSULIN-SECRETING PANCREATIC BETA-CELLS, TYPE 1 DIABETES HAS BEEN CALLED JUVENILE OR INSULIN-DEFICIENT DIABETES. IN TYPE 2, PATIENTS CAN STILL SECRETE SOME INSULIN BUT ITS EFFECTIVENESS MAY BE ATTENUATED BY 'INSULIN RESISTANCE.' THERE IS ALSO A GROUP OF RARE FORMS OF DIABETES IN THE YOUNG WHICH ARE INHERITED AS MONOGENETIC DISEASES. WHETHER ONE CALLS THE UNDERLYING PROCESS 'GENES VS. ENVIRONMENT' OR 'NATURE VS NURTURE', DIABETES OCCURS AT THE INTERFACE OF THE TWO DOMAINS. TOGETHER WITH OUR GENETIC BACKGROUND WE ARE BORN TABULA RASA-A BLANK SLATE UPON WHICH THE STORY OF LIFE, WITH ALL ITS ENVIRONMENTAL INPUTS WILL BE WRITTEN. THERE IS ONE PROVISO: THE INFLUENCE OF EPIGENETIC INHERITANCE MUST ALSO BE CONSIDERED. THUS, IN THE CREATION OF DATABASES THAT INCLUDE "BIG DATA" ORIGINATING FROM GENOMIC AS WELL AS EXPOSOME (DEFINED AS: THE TOTALITY OF ENVIRONMENTAL EXPOSURE FROM CONCEPTION TO DEATH), A BROAD PERSPECTIVE IS CRUCIAL AS THESE FACTORS ACT IN CONCERT IN SUCH CHRONIC ILLNESSES AS DIABETES THAT, FOR EXAMPLE, ARE LIKELY TO REQUIRE ADOPTION OF AN APPROPRIATE LIFESTYLE CHANGE. ALSO, IT IS BECOMING INCREASINGLY EVIDENT THAT EPIGENETIC FACTORS CAN MODULATE THE INTERPLAY BETWEEN GENES AND ENVIRONMENT. CONSEQUENTLY, THROUGHOUT THE LIFE OF AN INDIVIDUAL NATURE AND NURTURE INTERACT IN A COMPLEX MANNER IN THE DEVELOPMENT OF DIABETES. THIS REVIEW ADDRESSES THE QUESTION OF THE CONTRIBUTION OF GENE AND ENVIRONMENT AND THEIR INTERACTIONS IN THE DEVELOPMENT OF DIABETES. 2019 15 1824 24 EFFECTS OF ENVIRONMENTAL CONDITIONS ON NEPHRON NUMBER: MODELING MATERNAL DISEASE AND EPIGENETIC REGULATION IN RENAL DEVELOPMENT. A GROWING BODY OF EVIDENCE SUGGESTS THAT LOW NEPHRON NUMBERS AT BIRTH CAN INCREASE THE RISK OF CHRONIC KIDNEY DISEASE OR HYPERTENSION LATER IN LIFE. ENVIRONMENTAL STRESSORS, SUCH AS MATERNAL MALNUTRITION, MEDICATION AND SMOKING, CAN INFLUENCE RENAL SIZE AT BIRTH. USING METANEPHRIC ORGAN CULTURES TO MODEL SINGLE-VARIABLE ENVIRONMENTAL CONDITIONS, MODELS OF MATERNAL DISEASE WERE EVALUATED FOR PATTERNS OF DEVELOPMENTAL IMPAIRMENT. WHILE HYPERTHERMIA HAD LIMITED EFFECTS ON RENAL DEVELOPMENT, FETAL IRON DEFICIENCY WAS ASSOCIATED WITH SEVERE IMPAIRMENT OF RENAL GROWTH AND NEPHROGENESIS WITH AN ALL-PROXIMAL PHENOTYPE. CULTURING KIDNEY EXPLANTS UNDER HIGH GLUCOSE CONDITIONS LED TO CELLULAR AND TRANSCRIPTOMIC CHANGES RESEMBLING HUMAN DIABETIC NEPHROPATHY. SHORT-TERM HIGH GLUCOSE CULTURE CONDITIONS WERE SUFFICIENT FOR LONG-TERM ALTERATIONS IN DNA METHYLATION-ASSOCIATED EPIGENETIC MEMORY. FINALLY, THE ROLE OF EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT WAS TESTED USING A SMALL COMPOUND LIBRARY. AMONG THE SELECTED EPIGENETIC INHIBITORS, VARIOUS COMPOUNDS ELICITED AN EFFECT ON RENAL GROWTH, SUCH AS HDAC (ENTINOSTAT, TH39), HISTONE DEMETHYLASE (DEFERASIROX, DEFEROXAMINE) AND HISTONE METHYLTRANSFERASE (CYPROHEPTADINE) INHIBITORS. THUS, METANEPHRIC ORGAN CULTURES PROVIDE A VALUABLE SYSTEM FOR STUDYING METABOLIC CONDITIONS AND A TOOL FOR SCREENING FOR EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT. 2021 16 1974 29 EPIGENETIC ALTERATIONS CAUSED BY NUTRITIONAL STRESS DURING FETAL PROGRAMMING OF THE ENDOCRINE PANCREAS. NUTRITION DURING CRITICAL PERIODS OF DEVELOPMENT IS ONE OF THE PIVOTAL FACTORS IN ESTABLISHING A LIFELONG HEALTHY METABOLISM. DIFFERENT NUTRITIONAL DEFICIENCIES SUCH AS A LOW AVAILABILITY OF PROTEINS IN THE MATERNAL DIET PRODUCE ALTERATIONS IN OFFSPRING THAT INCLUDE CHANGES IN INSULIN AND GLUCOSE METABOLISM, A DECREASE IN THE SIZE AND NUMBER OF CELLS OF PANCREATIC ISLETS OF LANGERHANS, AND PREMATURE AGEING OF THE SECRETORY FUNCTION OF PANCREATIC BETA CELLS. MOREOVER, IT HAS BEEN REPORTED THAT CHRONIC NUTRITIONAL STRESS IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN MECHANISMS OF GENE REGULATION DURING PANCREATIC DEVELOPMENT AND FUNCTION. THESE ALTERATIONS CAN LEAD TO DYSFUNCTIONAL STATES IN PANCREATIC BETA CELLS, WHICH IN THE LONG RUN ARE RESPONSIBLE FOR THE ONSET OF METABOLIC DISEASES LIKE TYPE 2 DIABETES. THE PRESENT REVIEW SUMMARIZES THE MOST IMPORTANT EVIDENCE IN RELATION TO THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE REGULATION OF GENE EXPRESSION DURING THE INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS IN ANIMAL MODELS. SUCH MECHANISMS INCLUDE DNA METHYLATION AS WELL AS MODIFICATIONS OF HISTONES AND MICRORNAS (MIRNAS). 2015 17 6380 32 THE ROLE OF OBESITY AND DIABETES IN DEMENTIA. CHRONIC CONDITIONS SUCH AS OBESITY, DIABETES, AND DEMENTIA ARE INCREASING IN THE UNITED STATES (US) POPULATION. KNOWLEDGE OF THESE CHRONIC CONDITIONS, PREVENTATIVE MEASURES, AND PROPER MANAGEMENT TACTICS IS IMPORTANT AND CRITICAL TO PREVENTING DISEASE. THE OVERLAP BETWEEN OBESITY, DIABETES, AND DEMENTIA IS BECOMING FURTHER ELUCIDATED. THESE CONDITIONS SHARE A SIMILAR ORIGIN THROUGH THE COMPONENTS OF INCREASING AGE, GENDER, GENETIC AND EPIGENETIC PREDISPOSITIONS, DEPRESSION, AND A HIGH-FAT WESTERN DIET (WD) THAT ALL CONTRIBUTE TO THE INFLAMMATORY STATE ASSOCIATED WITH THE DEVELOPMENT OF OBESITY, DIABETES, AND DEMENTIA. THIS INFLAMMATORY STATE LEADS TO THE DYSREGULATION OF FOOD INTAKE AND INSULIN RESISTANCE. OBESITY IS OFTEN THE CORNERSTONE THAT LEADS TO THE DEVELOPMENT OF DIABETES AND, SUBSEQUENTLY, IN THE CASE OF TYPE 2 DIABETES MELLITUS (T2DM), PROGRESSION TO "TYPE 3 DIABETES MELLITUS (T3DM)". OBESITY AND DEPRESSION ARE CLOSELY ASSOCIATED WITH DIABETES. HOWEVER, DEMENTIA CAN BE AVOIDED WITH LIFESTYLE MODIFICATIONS, BY SWITCHING TO A PLANT-BASED DIET (E.G., A MEDITERRANEAN DIET (MD)), AND INCREASING PHYSICAL ACTIVITY. DIET AND EXERCISE ARE NOT THE ONLY TREATMENT OPTIONS. THERE ARE SEVERAL SURGICAL AND PHARMACOLOGICAL INTERVENTIONS AVAILABLE FOR PREVENTION. CURRENT AND FUTURE RESEARCH WITHIN EACH OF THESE FIELDS IS WARRANTED AND OFFERS THE CHANCE FOR NEW TREATMENT OPTIONS AND A BETTER UNDERSTANDING OF THE PATHOGENESIS OF EACH CONDITION. 2022 18 1241 26 CURRENT AND FUTURE NUTRITIONAL STRATEGIES TO MODULATE INFLAMMATORY DYNAMICS IN METABOLIC DISORDERS. OBESITY, TYPE 2 DIABETES, AND OTHER METABOLIC DISORDERS HAVE A LARGE IMPACT ON GLOBAL HEALTH, ESPECIALLY IN WESTERN COUNTRIES. AN IMPORTANT HALLMARK OF METABOLIC DISORDERS IS CHRONIC LOW-GRADE INFLAMMATION. A KEY PLAYER IN CHRONIC LOW-GRADE INFLAMMATION IS DYSMETABOLISM, WHICH IS DEFINED AS THE INABILITY TO KEEP HOMEOSTASIS RESULTING IN LOSS OF LIPID CONTROL, OXIDATIVE STRESS, INFLAMMATION, AND INSULIN RESISTANCE. ALTHOUGH OFTEN NOT YET DETECTABLE IN THE CIRCULATION, CHRONIC LOW-GRADE INFLAMMATION CAN BE PRESENT IN ONE OR MULTIPLE ORGANS. THE RESPONSE TO A METABOLIC CHALLENGE CONTAINING LIPIDS MAY MAGNIFY DYSFUNCTIONALITIES AT THE TISSUE LEVEL, CAUSING AN OVERFLOW OF INFLAMMATORY MARKERS INTO THE CIRCULATION AND HENCE ALLOW DETECTION OF EARLY LOW-GRADE INFLAMMATION. HERE, WE SUMMARIZE THE EVIDENCE OF SUCCESSFUL APPLICATION OF METABOLIC CHALLENGE TESTS IN TYPE 2 DIABETES, METABOLIC SYNDROME, OBESITY, AND UNHEALTHY AGING. WE ALSO REVIEW HOW METABOLIC CHALLENGE TESTS HAVE BEEN SUCCESSFULLY APPLIED TO EVALUATE NUTRITIONAL INTERVENTION EFFECTS, INCLUDING AN "ANTI-INFLAMMATORY" MIXTURE, DARK CHOCOLATE, WHOLE GRAIN WHEAT AND OVERFEEDING. ADDITIONALLY, WE ELABORATE ON FUTURE STRATEGIES TO (RE)GAIN INFLAMMATORY FLEXIBILITY. THROUGH EPIGENETIC AND METABOLIC REGULATION, THE INFLAMMATORY RESPONSE MAY BE TRAINED BY REGULAR MILD AND METABOLIC TRIGGERS, WHICH CAN BE UNDERSTOOD FROM THE PERSPECTIVE OF TRAINED IMMUNITY, HORMESIS AND PRO-RESOLUTION. NEW STRATEGIES TO OPTIMIZE DYNAMICS OF INFLAMMATION MAY BECOME AVAILABLE. 2019 19 4972 32 PATHOPHYSIOLOGICAL BASIS FOR COMPROMISED HEALTH BEYOND GENERATIONS: ROLE OF MATERNAL HIGH-FAT DIET AND LOW-GRADE CHRONIC INFLAMMATION. EARLY EXPOSURE TO A FAT-ENRICHED DIET PROGRAMS THE DEVELOPMENTAL PROFILE AND THUS IS ASSOCIATED WITH DISEASE SUSCEPTIBILITY IN SUBSEQUENT GENERATIONS. CHRONIC LOW-GRADE INFLAMMATION, RESULTING FROM MATERNAL HIGH-FAT DIET, IS ACTIVATED IN THE FETAL ENVIRONMENT AND IN MANY ORGANS OF OFFSPRING, INCLUDING PLACENTA, ADIPOSE, LIVER, VASCULAR SYSTEM AND BRAIN. THE PREVALENCE OF AN INFLAMMATORY RESPONSE IS HIGHLY ASSOCIATED WITH OBESITY INCIDENCE, CARDIOVASCULAR DISEASES, NONALCOHOLIC FATTY LIVER DISEASE AND BRAIN DAMAGE. SUBSTANTIAL STUDIES USING HIGH-FAT MODEL HAVE CONSISTENTLY DEMONSTRATED THE INCIDENCE OF SUCH INFLAMMATORY REACTIONS; HOWEVER, THE POTENTIAL CONTRIBUTION OF ACTIVE INFLAMMATION TOWARD THE PHYSIOLOGICAL OUTCOMES AND DEVELOPMENTAL DISEASES IS NEITHER DISCUSSED IN DEPTH NOR SYSTEMICALLY INTEGRATED. THEREFORE, WE AIM TO SUMMARIZE THE CURRENT FINDINGS IN REGARDS TO HOW A MATERNAL HIGH-FAT DIET INFLUENCES THE INFLAMMATORY STATUS, AND PROBABLE PATHOGENIC EFFECTS ON THE OFFSPRING. MORE IMPORTANTLY, SINCE LIMITED RESEARCH HAS BEEN CONDUCTED TO REVEAL THE EPIGENETIC REGULATION OF THESE INFLAMMATORY MARKERS BY MATERNAL HIGH-FAT DIET, WE SINCERELY HOPE THAT OUR REVIEW WILL NOT ONLY OUTLINE THE PATHOPHYSIOLOGICAL RELEVANCE OF INFLAMMATION BUT ALSO IDENTIFY A FUTURE DIRECTION FOR MECHANISTIC INVESTIGATION AND CLINICAL APPLICATION. 2015 20 44 29 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