1 1939 151 EPIDEMIOLOGY AND (PATHO)PHYSIOLOGY OF FOLIC ACID SUPPLEMENT USE IN OBESE WOMEN BEFORE AND DURING PREGNANCY. PRECONCEPTION FOLIC ACID SUPPLEMENT USE IS A WELL-KNOWN METHOD OF PRIMARY PREVENTION OF NEURAL TUBE DEFECTS (NTDS). OBESE WOMEN ARE AT A HIGHER RISK FOR HAVING A CHILD WITH A NTD. AS DIFFERENT INTERNATIONAL RECOMMENDATIONS ON FOLIC ACID SUPPLEMENT USE FOR OBESE WOMEN BEFORE AND DURING PREGNANCY EXIST, THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF EPIDEMIOLOGY OF FOLATE DEFICIENCY IN OBESE (PRE)PREGNANT WOMEN, ELABORATES ON POTENTIAL MECHANISMS UNDERLYING FOLATE DEFICIENCY, AND DISCUSSES CONSIDERATIONS FOR THE USAGE OF HIGHER DOSES OF FOLIC ACID SUPPLEMENTS. WOMEN WITH OBESITY MORE OFTEN SUFFER FROM AN ABSOLUTE FOLATE DEFICIENCY, AS THEY ARE LESS COMPLIANT TO PERICONCEPTIONAL FOLIC ACID SUPPLEMENT USE RECOMMENDATIONS. IN ADDITION, THEIR DIETARY FOLATE INTAKE IS LIMITED DUE TO AN UNBALANCED DIET (RELATIVE MALNUTRITION). THE ASSOCIATION OF OBESITY AND NTDS ALSO SEEMS TO BE INDEPENDENT OF FOLATE INTAKE, WITH STUDIES SUGGESTING AN INCREASED NEED OF FOLATE (RELATIVE DEFICIENCY) DUE TO DERANGEMENTS INVOLVED IN OTHER PATHWAYS. THE RELATIVE FOLATE DEFICIENCY, AS A RESULT OF AN INCREASED METABOLIC NEED FOR FOLATE IN OBESE WOMEN, CAN BE DUE TO: (1) LOW-GRADE CHRONIC INFLAMMATION (2) INSULIN RESISTANCE, (3) INOSITOL, AND (4) DYSBIOTIC GUT MICROBIOME, WHICH PLAYS A ROLE IN FOLATE PRODUCTION AND UPTAKE. IN ALL THESE PATHWAYS, THE FOLATE-DEPENDENT ONE-CARBON METABOLISM IS INVOLVED. IN CONCLUSION, SCIENTIFIC EVIDENCE OF THE INVOLVEMENT OF SEVERAL FOLATE-RELATED PATHWAYS IMPLIES TO INCREASE THE RECOMMENDED FOLIC ACID SUPPLEMENTATION IN OBESE WOMEN. HOWEVER, THE PHYSIOLOGICAL UPTAKE OF SYNTHETIC FOLIC ACID IS LIMITED AND SIDE-EFFECTS OF UNMETABOLIZED FOLIC ACID IN MOTHERS AND OFFSPRING, IN PARTICULAR VARIATIONS IN EPIGENETIC (RE)PROGRAMMING WITH LONG-TERM HEALTH EFFECTS, CANNOT BE EXCLUDED. THEREFORE, WE EMPHASIZE ON THE URGENT NEED FOR FURTHER RESEARCH AND PRECONCEPTION PERSONALIZED COUNSELING ON FOLATE STATUS, LIFESTYLE, AND MEDICAL CONDITIONS. 2021 2 1365 32 DEVELOPMENTAL ORIGIN OF CHRONIC DISEASES: TOXICOLOGICAL IMPLICATION. HUMAN EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES SHOW THAT SUBOPTIMAL ENVIRONMENTS IN FETAL AND NEONATAL LIFE EXERTS A PROFOUND INFLUENCE ON PHYSIOLOGICAL FUNCTION AND RISK OF DISEASE IN ADULT LIFE. THE MOLECULAR, CELLULAR, METABOLIC, ENDOCRINE AND PHYSIOLOGICAL ADAPTATIONS TO INTRAUTERINE NUTRITIONAL CONDITIONS RESULT IN PERMANENT ALTERATIONS OF CELLULAR PROLIFERATION AND DIFFERENTIATION OF TISSUES AND ORGAN SYSTEMS, WHICH IN TURN CAN MANIFEST BY PATHOLOGICAL CONSEQUENCES OR INCREASED VULNERABILITY TO CHRONIC DISEASES IN ADULTHOOD. INTRAUTERINE GROWTH RESTRICTION (IUGR) DUE TO INTRAUTERINE DEVELOPMENT DERANGEMENTS IS CONSIDERED THE IMPORTANT FACTOR IN DEVELOPMENT OF SUCH DISEASES AS ESSENTIAL HYPERTENSION, DIABETES MELLITUS, ISCHEMIC DISEASES OF THE HEART, OSTEOPOROSIS, RESPIRATORY, NEUROPSYCHIATRIC AND IMMUNE SYSTEM DISEASES.AN EARLY LIFE EXPOSURES TO DIETARY AND ENVIRONMENTAL EXPOSURES CAN HAVE A IMPORTANT EFFECT ON EPIGENETIC CODE, RESULTING IN DISEASES DEVELOPED LATER IN LIFE. THE CONCEPT OF THE "DEVELOPMENTAL PROGRAMMING" AND DEVELOPMENTAL ORIGINS OF ADULT DISEASES (DOHAD) HAS BECOME WELL ACCEPTED BECAUSE OF THE COMPELLING ANIMAL STUDIES THAT HAVE PRECISELY DEFINED THE OUTCOMES OF SPECIFIC EXPOSURES.THE ENVIRONMENTAL POLLULLUTANTS AND OTHER CHEMICAL TOXICANTS MAY INFLUENCE CRUCIAL CELLULAR FUNCTIONS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT AND PERMANENTLY ALTER THE STRUCTURE OR FUNCTION OF SPECIFIC ORGAN SYSTEMS. DEVELOPMENTAL EPIGENETICS IS BELIEVED TO ESTABLISH "ADAPTIVE" PHENOTYPES TO MEET THE DEMANDS OF THE LATER-LIFE ENVIRONMENT. RESULTING PHENOTYPES THAT MATCH PREDICTED LATER-LIFE DEMANDS WILL PROMOTE HEALTH, WHILE A HIGH DEGREE OF MISMATCH WILL IMPEDE ADAPTABILITY TO LATER-LIFE CHALLENGES AND ELEVATE DISEASE RISK. THE RAPID INTRODUCTION OF SYNTHETIC CHEMICALS, ENVIRONMENTAL POLLUTANTS AND MEDICAL INTERVENTIONS, MAY RESULT IN CONFLICT WITH THE PROGRAMMED ADAPTIVE CHANGES MADE DURING EARLY DEVELOPMENT, AND EXPLAIN THE ALARMING INCREASES IN SOME DISEASES. 2008 3 6305 48 THE QUESTION IS WHETHER INTAKE OF FOLIC ACID FROM DIET ALONE DURING PREGNANCY IS SUFFICIENT. PREGNANCY AND FOLIC ACID: PREGNANCY IS THE MOST IMPORTANT PERIOD IN LIFE OF EVERY WOMAN, PARTIALLY FOR THE NUMBER OF PHYSIOLOGICAL ADAPTATIONS SHE IS GOING THROUGH, PARTIALLY FOR THE EXPECTANCE OF NEW LIFE. IN ADDITION, PREGNANCY IS THE "CRITICAL WINDOW" FOR DEVELOPMENT LATER IN CHILDHOOD, AS A PERIOD OF FOETAL PROGRAMMING DURING WHICH NUTRITION PLAYS ONE OF CRUCIAL ROLES. DESPITE THE GENERAL BELIEF THAT NUTRITION THROUGH PREGNANCY IS ADEQUATE AND CHARACTERIZED BY BETTER NUTRITIONAL HABITS, A NUMBER OF STUDIES DO NOT CORROBORATE THIS BELIEF. ROLE OF FOLIC ACID: AN ADEQUATE FOLATE BLOOD LEVEL IS NECESSARY FOR NORMAL CELL GROWTH, SYNTHESIS OF SEVERAL COMPOUNDS INCLUDING DEOXYRIBONUCLEIC ACID AND RIBONUCLEIC ACID, PROPER BRAIN AND NEUROLOGIC FUNCTIONS; IT IS INCLUDED IN THE REGULATION OF HOMOCYSTEINE LEVEL, AND CLOSELY RELATED TO THE VITAMIN B12 METABOLISM. FOLATE DEFICIENCY IN PREGNANCY IS RELATED TO NEURAL TUBE DEFECTS, OTHER NEUROLOGICAL DISORDERS, PRETERM DELIVERY AND LOW BIRTH WEIGHT. FOOD SOURCES: A CORRELATION BETWEEN FOLATE AND THE PREVENTION OF BROAD SPECTRUM OF CHRONIC DISEASES HAS BEEN CONFIRMED. EMERGING EVIDENCE FROM THE EPIGENETIC STUDIES IS NOW BRINGING EVEN MORE LIGHT ON THE LEVEL OF SIGNIFICANCE OF FOLIC ACID. A WIDE RANGE OF PLANT AND ANIMAL FOODS ARE THE NATURAL SOURCES OF FOLATE; LIVER, YEAST, MUSHROOMS, AND GREEN LEAFY VEGETABLES BEING THE MOST SIGNIFICANT. DIFFERENT WAYS OF FOOD PREPARATION INFLUENCE THE FOLATE STABILITY AND ITS BIOAVAILABILITY VARIES FROM 25 TO 50% FROM FOODS, 85% FROM ENRICHED FOODS OR 100% FROM SUPPLEMENTS. CONCLUSION: A GREAT AMOUNT OF SCIENTIFIC RESULTS HAS LED TO OFFICIAL RECOMMENDATIONS FOR FOLIC ACID SUPPLEMENTATION IN PREGNANT WOMEN AS WELL AS IN A NUMBER OF OBLIGATORY OR VOLUNTARY FORTIFICATION PROGRAMMES IN ORDER TO PREVENT THE FOLATE DEFICIENCY ON THE LEVEL OF DIFFERENT POPULATION GROUPS. NEVERTHELESS, THERE MUST BE A CERTAIN LEVEL OF PRECAUTION FOR ELDERLY BECAUSE FOLATE CAN MASK THE VITAMIN B12 DEFICIENCY WITH POSSIBLE FATAL OUTCOMES. 2014 4 3595 32 IMPLICATIONS OF MATERNAL CONDITIONS AND PREGNANCY COURSE ON OFFSPRING'S MEDICAL PROBLEMS IN ADULT LIFE. IN THE LAST DECADE, NUMEROUS EPIDEMIOLOGICAL, CLINICAL AND EXPERIMENTAL DATA SHOW THAT PERICONCEPTIONAL, PERINATAL AND POSTNATAL ENVIRONMENT DETERMINES THE OFFSPRING'S RISK FOR LATER-LIFE CHRONIC DISEASE. FOR THIS PHENOMENON, THE TERM "FETAL" OR "PERINATAL PROGRAMMING" IS USED. IN EXPOSED OFFSPRING ALREADY IN CHILDHOOD AND EARLY ADULTHOOD, METABOLIC AND CARDIOVASCULAR CHANGES CAN BE OBSERVED, LEADING TO OBESITY, DIABETES AND HYPERTENSION. NOWADAYS, THE MODE OF CONCEPTION (E.G., IN VITRO FERTILIZATION), MATERNAL METABOLIC CONDITIONS (E.G., UNDERNUTRITION, OVERNUTRITION, DIABETES) AND COMPLICATIONS DURING PREGNANCY (E.G., PREECLAMPSIA, INTRAUTERINE GROWTH RESTRICTION) ARE SUSPECTED TO BE NEGATIVE PREDICTORS FOR OFFSPRING'S LONG-TERM HEALTH. MECHANISMS RESPONSIBLE FOR THESE EFFECTS STILL REMAIN MAINLY UNCLEAR, BUT INCLUDE EPIGENETIC, TRANSCRIPTIONAL, ENDOPLASMIC RETICULUM STRESS, AND REACTIVE OXYGEN SPECIES. THIS REVIEW PRESENTS A PIECE OF THE PUZZLE WITH REGARDS TO PERICONCEPTIONAL AND EARLY PERINATAL CONDITIONS DETERMINING LATER-LIFE RISK FOR CHRONIC ADULT DISEASE. 2016 5 2805 42 FETAL MALNUTRITION AND LONG-TERM OUTCOMES. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT LOWER BIRTHWEIGHT IS ASSOCIATED WITH A WIDE RANGE OF ADVERSE OUTCOMES IN LATER LIFE, INCLUDING POORER 'HUMAN CAPITAL' (SHORTER STATURE, LOWER COGNITIVE PERFORMANCE), INCREASED RISK FACTORS FOR LATER DISEASE (HIGHER BLOOD PRESSURE AND REDUCED GLUCOSE TOLERANCE, AND LUNG, KIDNEY AND IMMUNE FUNCTION), CLINICAL DISEASE (DIABETES, CORONARY HEART DISEASE, CHRONIC LUNG AND KIDNEY DISEASE), AND INCREASED ALL-CAUSE AND CARDIOVASCULAR MORTALITY. HIGHER BIRTHWEIGHT IS ASSOCIATED WITH AN INCREASED RISK OF CANCER AND (IF CAUSED BY GESTATIONAL DIABETES) OBESITY AND DIABETES. THE 'DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE' HYPOTHESIS PROPOSES THAT FETAL NUTRITION HAS PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM ('PROGRAMMING'). THIS IS SUPPORTED BY STUDIES IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVERNUTRITION DURING PREGNANCY CAN PRODUCE SIMILAR ABNORMALITIES IN THE ADULT OFFSPRING. COMMON CHRONIC DISEASES COULD POTENTIALLY BE PREVENTED BY ACHIEVING OPTIMAL FETAL NUTRITION, AND THIS COULD HAVE ADDITIONAL BENEFITS FOR SURVIVAL AND HUMAN CAPITAL. RECENT FOLLOW-UP OF CHILDREN BORN AFTER RANDOMIZED NUTRITIONAL INTERVENTIONS IN PREGNANCY PROVIDES WEAK EVIDENCE OF BENEFICIAL EFFECTS ON GROWTH, VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. ANIMAL STUDIES INDICATE THAT EPIGENETIC PHENOMENA MAY BE AN IMPORTANT MECHANISM UNDERLYING PROGRAMMING, AND THAT NUTRITIONAL INTERVENTIONS MAY NEED TO START PRECONCEPTIONALLY. 2013 6 1412 44 DIETARY PATTERNS INFLUENCE TARGET GENE EXPRESSION THROUGH EMERGING EPIGENETIC MECHANISMS IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) REFERS TO THE PATHOLOGIC BUILDUP OF EXTRA FAT IN THE FORM OF TRIGLYCERIDES IN LIVER CELLS WITHOUT EXCESSIVE ALCOHOL INTAKE. NAFLD BECAME THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE THAT IS TIGHTLY ASSOCIATED WITH KEY ASPECTS OF METABOLIC DISORDERS, INCLUDING INSULIN RESISTANCE, OBESITY, DIABETES, AND METABOLIC SYNDROME. IT IS GENERALLY ACCEPTED THAT MULTIPLE MECHANISMS AND PATHWAYS ARE INVOLVED IN THE PATHOGENESIS OF NAFLD. HEREDITY, SEDENTARY LIFESTYLE, WESTERNIZED HIGH SUGAR SATURATED FAT DIET, METABOLIC DERANGEMENTS, AND GUT MICROBIOTA, ALL MAY INTERACT ON A ON GENETICALLY SUSCEPTIBLE INDIVIDUAL TO CAUSE THE DISEASE INITIATION AND PROGRESSION. WHILE THERE IS AN UNQUESTIONABLE ROLE FOR GENE-DIET INTERACTION IN THE ETIOPATHOGENESIS OF NAFLD, IT IS INCREASINGLY APPARENT THAT EPIGENETIC PROCESSES CAN ORCHESTRATE MANY ASPECTS OF THIS INTERACTION AND PROVIDE ADDITIONAL MECHANISTIC INSIGHT. EXCITING RESEARCH DEMONSTRATED THAT EPIGENETIC ALTERATIONS IN CHROMATIN CAN INFLUENCE GENE EXPRESSION CHIEFLY AT THE TRANSCRIPTIONAL LEVEL IN RESPONSE TO UNBALANCED DIET, AND THEREFORE PREDISPOSE AN INDIVIDUAL TO NAFLD. THUS, FURTHER DISCOVERIES INTO MOLECULAR EPIGENETIC MECHANISMS UNDERLYING THE LINK BETWEEN NUTRITION AND ABERRANT HEPATIC GENE EXPRESSION CAN YIELD NEW INSIGHTS INTO THE PATHOGENESIS OF NAFLD, AND ALLOW INNOVATIVE EPIGENETIC-BASED STRATEGIES FOR ITS EARLY PREVENTION AND TARGETED THERAPIES. HEREIN, WE OUTLINE THE CURRENT KNOWLEDGE OF THE INTERACTIVE ROLE OF A HIGH-FAT HIGH-CALORIES DIET AND GENE EXPRESSION THROUGH DNA METHYLATION AND HISTONE MODIFICATIONS ON THE PATHOGENESIS OF NAFLD. WE ALSO PROVIDE PERSPECTIVES ON THE ADVANCEMENT OF THE EPIGENOMICS IN THE FIELD AND POSSIBLE SHORTCOMINGS AND LIMITATIONS AHEAD. 2021 7 5203 29 PRENATAL PROGRAMMING AND EPIGENETICS IN THE GENESIS OF THE CARDIORENAL SYNDROME. THE PRESENCE OF A GROUP OF INTERACTING MALADAPTIVE FACTORS, INCLUDING HYPERTENSION, INSULIN RESISTANCE, METABOLIC DYSLIPIDEMIA, OBESITY, AND MICROALBUMINURIA AND/OR REDUCED RENAL FUNCTION, COLLECTIVELY CONSTITUTES THE CARDIORENAL METABOLIC SYNDROME (CRS). NUTRITIONAL AND OTHER ENVIRONMENTAL CUES DURING FETAL DEVELOPMENT CAN PERMANENTLY AFFECT THE COMPOSITION, HOMEOSTATIC SYSTEMS, AND FUNCTIONS OF MULTIPLE ORGANS AND SYSTEMS; THIS PROCESS HAS BEEN REFERRED TO AS 'PROGRAMMING'. SINCE THE ORIGINAL FORMULATION OF THE NOTION THAT LOW BIRTH WEIGHT IS A PROXY FOR 'PRENATAL PROGRAMMING' OF ADULT HYPERTENSION AND CARDIOVASCULAR DISEASE, EVIDENCE HAS ALSO EMERGED FOR PROGRAMMING OF KIDNEY DISEASE, INSULIN RESISTANCE, OBESITY, METABOLIC DYSLIPIDEMIA, AND OTHER CHRONIC DISEASES. THE PROGRAMMING CONCEPT WAS INITIALLY PREDICATED ON THE NOTION THAT IN UTERO GROWTH RESTRICTION DUE TO FAMINE WAS RESPONSIBLE FOR INCREASED HYPERTENSION, AND CARDIOVASCULAR AND RENAL DISEASES. ON THE OTHER HAND, WE ARE NOW MORE COMMONLY EXPOSED TO INCREASING RATES OF MATERNAL OBESITY. THE CURRENT REVIEW WILL DISCUSS THE OVERARCHING ROLE OF MATERNAL OVERNUTRITION, AS WELL AS FETAL UNDERNUTRITION, IN EPIGENETIC PROGRAMMING IN RELATION TO THE PATHOGENESIS OF THE CRS IN CHILDREN AND ADULTS. 2011 8 2806 39 FETAL PROGRAMMING AND THE RISK OF NONCOMMUNICABLE DISEASE. THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) HYPOTHESIS PROPOSES THAT ENVIRONMENTAL CONDITIONS DURING FETAL AND EARLY POST-NATAL DEVELOPMENT INFLUENCE LIFELONG HEALTH AND CAPACITY THROUGH PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM. THIS HAS BEEN CALLED 'PROGRAMMING'. THE HYPOTHESIS IS SUPPORTED BY EPIDEMIOLOGICAL EVIDENCE IN HUMANS LINKING NEWBORN SIZE, AND INFANT GROWTH AND NUTRITION, TO ADULT HEALTH OUTCOMES, AND BY EXPERIMENTS IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVER-NUTRITION AND OTHER INTERVENTIONS (E.G., GLUCOCORTICOID EXPOSURE) DURING PREGNANCY LEAD TO ABNORMAL METABOLISM AND BODY COMPOSITION IN THE ADULT OFFSPRING. EARLY LIFE PROGRAMMING IS NOW THOUGHT TO BE IMPORTANT IN THE ETIOLOGY OF OBESITY, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE, OPENING UP THE POSSIBILITY THAT THESE COMMON DISEASES COULD BE PREVENTED BY ACHIEVING OPTIMAL FETAL AND INFANT DEVELOPMENT. THIS IS LIKELY TO HAVE ADDITIONAL BENEFITS FOR INFANT SURVIVAL AND HUMAN CAPITAL (E.G., IMPROVED COGNITIVE PERFORMANCE AND PHYSICAL WORK CAPACITY). FETAL NUTRITION IS INFLUENCED BY THE MOTHER'S DIET AND BODY SIZE AND COMPOSITION, BUT HARD EVIDENCE THAT THE NUTRITION OF THE HUMAN MOTHER PROGRAMMES CHRONIC DISEASE RISK IN HER OFFSPRING IS CURRENTLY LIMITED. RECENT FINDINGS FROM FOLLOW-UP OF CHILDREN BORN AFTER RANDOMISED NUTRITIONAL INTERVENTIONS IN PREGNANCY ARE MIXED, BUT SHOW SOME EVIDENCE OF BENEFICIAL EFFECTS ON VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. WORK IN EXPERIMENTAL ANIMALS SUGGESTS THAT EPIGENETIC PHENOMENA, WHEREBY GENE EXPRESSION IS MODIFIED BY DNA METHYLATION, AND WHICH ARE SENSITIVE TO THE NUTRITIONAL ENVIRONMENT IN EARLY LIFE, MAY BE ONE MECHANISM UNDERLYING PROGRAMMING. 2013 9 4863 42 ORIGINS OF LIFETIME HEALTH AROUND THE TIME OF CONCEPTION: CAUSES AND CONSEQUENCES. PARENTAL ENVIRONMENTAL FACTORS, INCLUDING DIET, BODY COMPOSITION, METABOLISM, AND STRESS, AFFECT THE HEALTH AND CHRONIC DISEASE RISK OF PEOPLE THROUGHOUT THEIR LIVES, AS CAPTURED IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT. RESEARCH ACROSS THE EPIDEMIOLOGICAL, CLINICAL, AND BASIC SCIENCE FIELDS HAS IDENTIFIED THE PERIOD AROUND CONCEPTION AS BEING CRUCIAL FOR THE PROCESSES MEDIATING PARENTAL INFLUENCES ON THE HEALTH OF THE NEXT GENERATION. DURING THIS TIME, FROM THE MATURATION OF GAMETES THROUGH TO EARLY EMBRYONIC DEVELOPMENT, PARENTAL LIFESTYLE CAN ADVERSELY INFLUENCE LONG-TERM RISKS OF OFFSPRING CARDIOVASCULAR, METABOLIC, IMMUNE, AND NEUROLOGICAL MORBIDITIES, OFTEN TERMED DEVELOPMENTAL PROGRAMMING. WE REVIEW PERICONCEPTIONAL INDUCTION OF DISEASE RISK FROM FOUR BROAD EXPOSURES: MATERNAL OVERNUTRITION AND OBESITY; MATERNAL UNDERNUTRITION; RELATED PATERNAL FACTORS; AND THE USE OF ASSISTED REPRODUCTIVE TREATMENT. STUDIES IN BOTH HUMANS AND ANIMAL MODELS HAVE DEMONSTRATED THE UNDERLYING BIOLOGICAL MECHANISMS, INCLUDING EPIGENETIC, CELLULAR, PHYSIOLOGICAL, AND METABOLIC PROCESSES. WE ALSO PRESENT A META-ANALYSIS OF MOUSE PATERNAL AND MATERNAL PROTEIN UNDERNUTRITION THAT SUGGESTS DISTINCT PARENTAL PERICONCEPTIONAL CONTRIBUTIONS TO POSTNATAL OUTCOMES. WE PROPOSE THAT THE EVIDENCE FOR PERICONCEPTIONAL EFFECTS ON LIFETIME HEALTH IS NOW SO COMPELLING THAT IT CALLS FOR NEW GUIDANCE ON PARENTAL PREPARATION FOR PREGNANCY, BEGINNING BEFORE CONCEPTION, TO PROTECT THE HEALTH OF OFFSPRING. 2018 10 6819 37 [FETAL PROGRAMMING OF METABOLIC DISORDERS]. OUR KNOWLEDGE OF FETAL PROGRAMMING HAS DEVELOPED NOTABLY OVER THE YEARS AND RECENT DATA SUGGEST THAT AN UNBALANCED DIET PRIOR AND DURING PREGNANCY CAN HAVE EARLY-ONSET AND LONG-LASTING CONSEQUENCES ON THE HEALTH OF THE OFFSPRING. SPECIFIC NEGATIVE INFLUENCES OF HIGH DIETARY GLUCOSE AND LIPID CONSUMPTION, AS WELL AS UNDERNUTRITION, ARE ASSOCIATED WITH DEVELOPMENT OF METABOLIC SYNDROME, INSULIN RESISTANCE AND DIABETES IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE EFFECTS OF MATERNAL HYPERGLYCEMIA ON THE FETUS MAY INVOLVE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES. THE AIM OF THIS REVIEW IS TO ILLUSTRATE HOW ADVERSE INTRAUTERINE ENVIRONMENT MAY INFLUENCE MOLECULAR MODIFICATIONS IN THE FETUS AND CAUSE EPIGENETIC ALTERATIONS IN PARTICULAR. IT HAS BEEN DEMONSTRATED THAT PRENATAL EPIGENETIC MODIFICATIONS MAY BE LINKED TO THE PATHOGENESIS AND PROGRESSION OF THE ADULT CHRONIC DISORDERS. STUDIES ON EPIGENETIC ALTERATIONS WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE LONG-TERM EFFECTS OF IN UTERO EXPOSURE AND MAY OPEN NEW PERSPECTIVES FOR DISEASE PREVENTION AND TREATMENT. 2015 11 2098 40 EPIGENETIC EFFECTS OF HUMAN BREAST MILK. A CURRENT AIM OF NUTRIGENETICS IS TO PERSONALIZE NUTRITIONAL PRACTICES ACCORDING TO GENETIC VARIATIONS THAT INFLUENCE THE WAY OF DIGESTION AND METABOLISM OF NUTRIENTS INTRODUCED WITH THE DIET. NUTRITIONAL EPIGENETICS CONCERNS KNOWLEDGE ABOUT THE EFFECTS OF NUTRIENTS ON GENE EXPRESSION. NUTRITION IN EARLY LIFE OR IN CRITICAL PERIODS OF DEVELOPMENT, MAY HAVE A ROLE IN MODULATING GENE EXPRESSION, AND, THEREFORE, HAVE LATER EFFECTS ON HEALTH. HUMAN BREAST MILK IS WELL-KNOWN FOR ITS ABILITY IN PREVENTING SEVERAL ACUTE AND CHRONIC DISEASES. INDEED, BREASTFED CHILDREN MAY HAVE LOWER RISK OF NEONATAL NECROTIZING ENTEROCOLITIS, INFECTIOUS DISEASES, AND ALSO OF NON-COMMUNICABLE DISEASES, SUCH AS OBESITY AND RELATED-DISORDERS. BENEFICIAL EFFECTS OF HUMAN BREAST MILK ON HEALTH MAY BE ASSOCIATED IN PART WITH ITS PECULIAR COMPONENTS, POSSIBLE ALSO VIA EPIGENETIC PROCESSES. THIS PAPER DISCUSSES ABOUT PRESUMED EPIGENETIC EFFECTS OF HUMAN BREAST MILK AND COMPONENTS. WHILE EVIDENCE SUGGESTS THAT A DIRECT RELATIONSHIP MAY EXIST OF SOME COMPONENTS OF HUMAN BREAST MILK WITH EPIGENETIC CHANGES, THE MECHANISMS INVOLVED ARE STILL UNCLEAR. STUDIES HAVE TO BE CONDUCTED TO CLARIFY THE ACTUAL ROLE OF HUMAN BREAST MILK ON GENETIC EXPRESSION, IN PARTICULAR WHEN LINKED TO THE RISK OF NON-COMMUNICABLE DISEASES, TO POTENTIALLY BENEFIT THE INFANT'S HEALTH AND HIS LATER LIFE. 2014 12 1153 43 CONSEQUENCES OF PATERNAL NUTRITION ON OFFSPRING HEALTH AND DISEASE. IT IS WELL ESTABLISHED THAT THE MATERNAL DIET DURING THE PERICONCEPTIONAL PERIOD AFFECTS THE PROGENY'S HEALTH. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE PATERNAL DIET ALSO INFLUENCES DISEASE ONSET IN OFFSPRING. FOR MANY YEARS, SPERM WAS CONSIDERED ONLY TO CONTRIBUTE HALF OF THE PROGENY'S GENOME. IT NOW APPEARS THAT IT ALSO PLAYS A CRUCIAL ROLE IN HEALTH AND DISEASE IN OFFSPRING'S ADULT LIFE. THE NUTRITIONAL STATUS AND ENVIRONMENTAL EXPOSURE OF FATHERS DURING THEIR CHILDHOOD AND/OR THE PERICONCEPTIONAL PERIOD HAVE SIGNIFICANT TRANSGENERATIONAL CONSEQUENCES. THIS REVIEW AIMS TO DESCRIBE THE EFFECTS OF VARIOUS HUMAN AND RODENT PATERNAL FEEDING PATTERNS ON PROGENY'S METABOLISM AND HEALTH, INCLUDING FASTING OR INTERMITTENT FASTING, LOW-PROTEIN AND FOLIC ACID DEFICIENT FOOD, AND OVERNUTRITION IN HIGH-FAT AND HIGH-SUGAR DIETS. THE IMPACT ON PREGNANCY OUTCOME, METABOLIC PATHWAYS, AND CHRONIC DISEASE ONSET WILL BE DESCRIBED. THE BIOLOGICAL AND EPIGENETIC MECHANISMS UNDERLYING THE TRANSMISSION FROM FATHERS TO THEIR PROGENY WILL BE DISCUSSED. ALL THESE DATA PROVIDE EVIDENCE OF THE IMPACT OF PATERNAL NUTRITION ON PROGENY HEALTH WHICH COULD LEAD TO PREVENTIVE DIET RECOMMENDATIONS FOR FUTURE FATHERS. 2021 13 6873 38 [PREVENTION OF OBESITY FROM PERINATAL STAGE]. OBESITY IS ONE OF THE MAJOR HEALTH PROBLEMS AND A DETERMINING FACTOR IN THE PREVALENCE OF DISEASES SUCH AS METABOLIC SYNDROME, ASTHMA, SLEEP APNEA, INFERTILITY AND VARIOUS TYPES OF CANCER. ITS ORIGIN IS MULTIFACTORIAL, INVOLVING GENETIC, SOCIOECONOMIC AND ENVIRONMENTAL FACTORS. THESE LAST ONES CONTRIBUTE MOSTLY TO EXPLAIN THE CURRENT EPIDEMIC GROWTH OF THIS DISEASE. THE SEDENTARY LIFESTYLE, INADEQUATE DIET, LACK OF SLEEP, ALTERATIONS IN INTESTINAL MICROBIOTA AND STRESS ARE FACTORS RELATED TO ITS DEVELOPMENT. SINCE BARKER PRESENTED HIS HYPOTHESIS ABOUT THE "FETAL ORIGIN OF ADULT DISEASES", THERE ARE INCREASING NUMBER OF STUDIES THAT SHOW THE INFLUENCE OF AN INADEQUATE NUTRITIONAL STATUS AND MATERNAL WEIGHT IN THE DEVELOPMENT OF CHRONIC DISEASES, AS OBESITY IN OFFSPRING. THE NUTRITIONAL DEFICIENCIES OF THE PREGNANT MOTHER CAUSE EPIGENETIC MODIFICATIONS AND ABNORMAL PROGRAMMING OF THE DEVELOPMENT OFORGANS AND DEVICES, ADAPTING THE FETUS TO THIS SITUATION OF DEFICIENCY AND BEING ABLE TO ADAPT TO AN OBESOGENIC ENVIRONMENT AFTER BIRTH, INCREASING ITS PROPENSITY TO OBESITY. ALSO, POOR MATERNAL NUTRITIONAL STATUS IS RELATED TO INTRAUTERINE GROWTH RETARDATION AND LOW BIRTH WEIGHT INFANTS, WITH A HIGHER RISK OF CHILDHOOD AND ADULT CENTRAL OBESITY. CURRENTLY, DEFICIENT INTAKE OF MICRONUTRIENTS AND OVERWEIGHT OR MATERNAL OBESITY TEND TO OVERLAP, AND THIS COMBINATION MAY EXACERBATE THE INCREASE IN OBESITY IN THE OFFSPRING. IT IS IMPORTANT TO IDENTIFY PREGNANT MOTHERS AT RISK OF SUFFERING NUTRITIONAL ALTERATIONS AND ESTABLISH THEIR IMPROVEMENT AS A PRIMARY PREVENTION STRATEGY FOR OVERWEIGHT AND OBESITY. 2017 14 3817 28 INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS. EPIDEMIOLOGICAL STUDIES HAVE REVEALED STRONG RELATIONSHIPS BETWEEN POOR FOETAL GROWTH AND SUBSEQUENT DEVELOPMENT OF THE METABOLIC SYNDROME. PERSISTING EFFECTS OF EARLY MALNUTRITION BECOME TRANSLATED INTO PATHOLOGY, THEREBY DETERMINE CHRONIC RISK FOR DEVELOPING GLUCOSE INTOLERANCE AND DIABETES. THESE EPIDEMIOLOGICAL OBSERVATIONS IDENTIFY THE PHENOMENA OF FOETAL PROGRAMMING WITHOUT EXPLAINING THE UNDERLYING MECHANISMS THAT ESTABLISH THE CAUSAL LINK. ANIMAL MODELS HAVE BEEN ESTABLISHED AND STUDIES HAVE DEMONSTRATED THAT REDUCTION IN THE AVAILABILITY OF NUTRIENTS DURING FOETAL DEVELOPMENT PROGRAMS THE ENDOCRINE PANCREAS AND INSULIN-SENSITIVE TISSUES. WHATEVER THE TYPE OF FOETAL MALNUTRITION, WHETHER THERE ARE NOT ENOUGH CALORIES OR PROTEIN IN FOOD OR AFTER PLACENTAL DEFICIENCY, MALNOURISHED PUPS ARE BORN WITH A DEFECT IN THEIR BETA-CELL POPULATION THAT WILL NEVER COMPLETELY RECOVER, AND INSULIN-SENSITIVE TISSUES WILL BE DEFINITIVELY ALTERED. DESPITE THE SIMILAR ENDPOINT, DIFFERENT CELLULAR AND PHYSIOLOGICAL MECHANISMS ARE PROPOSED. HORMONES OPERATIVE DURING FOETAL LIFE LIKE INSULIN ITSELF, INSULIN-LIKE GROWTH FACTORS AND GLUCOCORTICOIDS, AS WELL AS SPECIFIC MOLECULES LIKE TAURINE, OR ISLET VASCULARIZATION WERE IMPLICATED AS POSSIBLE FACTORS AMPLIFYING THE DEFECT. THE MOLECULAR MECHANISMS RESPONSIBLE FOR INTRAUTERINE PROGRAMMING OF THE BETA CELLS ARE STILL ELUSIVE, BUT TWO HYPOTHESES RECENTLY EMERGED: THE FIRST ONE IMPLIES PROGRAMMING OF MITOCHONDRIA AND THE SECOND, EPIGENETIC REGULATION. 2007 15 751 25 CARDIOMETABOLIC EFFECTS OF POSTNATAL HIGH-FAT DIET CONSUMPTION IN OFFSPRING EXPOSED TO MATERNAL PROTEIN RESTRICTION IN UTERO. IN RECENT DECADES, THE HIGH INCIDENCE OF INFECTIOUS AND PARASITIC DISEASES HAS BEEN REPLACED BY A HIGH PREVALENCE OF CHRONIC AND DEGENERATIVE DISEASES. CONCOMITANTLY, THERE HAVE BEEN PROFOUND CHANGES IN THE BEHAVIOR AND EATING HABITS OF FAMILIES AROUND THE WORLD, CHARACTERIZING A "NUTRITIONAL TRANSITION" PHENOMENON, WHICH REFERS TO A SHIFT IN DIET IN RESPONSE TO MODERNIZATION, URBANIZATION, OR ECONOMIC DEVELOPMENT FROM UNDERNUTRITION TO THE EXCESSIVE CONSUMPTION OF HYPERCALORIC AND ULTRA-PROCESSED FOODS. PROTEIN MALNUTRITION THAT WAS A HEALTH PROBLEM IN THE FIRST HALF OF THE 20TH CENTURY HAS NOW BEEN REPLACED BY HIGH-FAT DIETS, ESPECIALLY DIETS HIGH IN SATURATED FAT, PREDISPOSING CONSUMERS TO OVERWEIGHT AND OBESITY. THIS PANORAMA POINTS US TO THE ALARMING COEXISTENCE OF BOTH MALNUTRITION AND OBESITY IN THE SAME POPULATION. IN THIS WAY, INDIVIDUALS WHOSE MOTHERS WERE UNDERNOURISHED EARLY IN PREGNANCY AND THEN EXPOSED TO POSTNATAL HYPERLIPIDIC NUTRITION HAVE INCREASED RISK FACTORS FOR DEVELOPING METABOLIC DYSFUNCTION AND CARDIOVASCULAR DISEASES IN ADULTHOOD. THUS, OUR MAJOR AIM WAS TO REVIEW THE CARDIOMETABOLIC EFFECTS RESULTING FROM POSTNATAL HYPERLIPIDIC DIETS IN PROTEIN-RESTRICTED SUBJECTS, AS WELL AS TO EXAMINE THE EPIGENETIC REPERCUSSIONS OCCASIONED BY THE NUTRITIONAL TRANSITION. 2022 16 4084 31 MATERNAL NUTRITION DURING PREGNANCY AND HEALTH OF THE OFFSPRING. THE ABILITY OF MOTHER TO PROVIDE NUTRIENTS AND OXYGEN FOR HER BABY IS A CRITICAL FACTOR FOR FETAL HEALTH AND ITS SURVIVAL. FAILURE IN SUPPLYING THE ADEQUATE AMOUNT OF NUTRIENTS TO MEET FETAL DEMAND CAN LEAD TO FETAL MALNUTRITION. THE FETUS RESPONDS AND ADAPTS TO UNDERNUTRITION BUT BY DOING SO IT PERMANENTLY ALTERS THE STRUCTURE AND FUNCTION OF THE BODY. MATERNAL OVERNUTRITION ALSO HAS LONG-LASTING AND DETRIMENTAL EFFECTS ON THE HEALTH OF THE OFFSPRING. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITION CAN INDUCE EPIGENETIC MODIFICATIONS OF THE FETAL GENOME. ONLY RELATIVELY RECENTLY HAS EVIDENCE FROM EPIDEMIOLOGICAL AND ANIMAL STUDIES EMERGED SUGGESTING THAT FETAL RESPONSES TO THE INTRAUTERINE ENVIRONMENT MAY UNDERLIE THE PREVALENCE OF MANY CHRONIC DISEASES OF ADULTHOOD INCLUDING TYPE 2 (NON-INSULIN-DEPENDENT) DIABETES. IT IS NOW OF CRUCIAL IMPORTANCE TO GAIN THE UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN FETAL ALTERATIONS TO THE INTRA-UTERINE ENVIRONMENT AND THEIR LONG-TERM EFFECTS ON THE HEALTH OF AN INDIVIDUAL. 2006 17 5190 27 PRENATAL CAUSES OF KIDNEY DISEASE. IT HAS RECENTLY BEEN INCREASINGLY RECOGNISED THAT DISTURBED INTRA-UTERINE DEVELOPMENT MAY IMPACT ON RENAL AND CARDIOVASCULAR RISK IN ADULT LIFE, E.G. ALBUMINURIA AND CHRONIC KIDNEY DISEASE, HYPERTENSION, TYPE 2 DIABETES OR CARDIOVASCULAR EVENTS. ACCORDING TO BARKER'S HYPOTHESIS, WHEN RESOURCES IN UTERO ARE RESTRICTED, THEIR ALLOCATION TO THE DEVELOPMENT OF THE KIDNEY AND PANCREATIC ISLETS IS RESTRICTED TO GUARANTEE APPROPRIATE DEVELOPMENT OF THE BRAIN AND HEART. THE UNDERLYING EPIGENETIC MECHANISMS INVOLVE MODIFICATION OF GENE EXPRESSION BY ALTERED DNA METHYLATION AND HISTONE ACETYLATION AS WELL AS BY ALLOCATION OF STEM CELLS. THE RESULT OF THIS TRADE-OFF BETWEEN THE BRAIN AND KIDNEY DURING ORGANOGENESIS IS A DIMINISHED NUMBER OF NEPHRONS ('NEPHRON UNDERDOSING') WHICH PREDISPOSES TO ALBUMINURIA AND RISK OF CHRONIC KIDNEY DISEASE, AS WELL AS HYPERTENSION. IN PARALLEL, CHANGED APPETITE CENTRES, INSULIN RESISTANCE AND BETA-CELL DEVELOPMENT PREDISPOSE TO OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES AND THE RESULTING RENAL SEQUELAE. NUMEROUS FACTORS MAY TRIGGER INTRA-UTERINE RESTRICTION OF FETAL GROWTH, SUCH AS UTERINE UNDERPERFUSION, MATERNAL MALNUTRITION, HYPERGLYCAEMIA AND HYPERINSULINAEMIA OF THE MOTHER, SMOKING OR MEDICATIONS. 2009 18 4711 42 NON-ALCOHOLIC FATTY LIVER DISEASE IN OBESE CHILDREN AND ADOLESCENTS: A ROLE FOR NUTRITION? NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BECOME THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN, PARALLELING THE INCREASING PREVALENCE OF OBESITY WORLDWIDE. THE PATHOGENESIS OF PAEDIATRIC NAFLD IS NOT FULLY UNDERSTOOD, BUT IT IS KNOWN THAT OBESITY, NUTRITION, LIFESTYLE VARIABLES, GENETIC AND EPIGENETIC FACTORS MAY BE CAUSALLY INVOLVED IN THE DEVELOPMENT OF THIS COMMON METABOLIC LIVER DISEASE. IN PARTICULAR, OBESITY AND NUTRITION ARE AMONG THE STRONGEST RISK FACTORS FOR PAEDIATRIC NAFLD, WHICH MAY EXERT THEIR ADVERSE HEPATIC EFFECTS ALREADY BEFORE BIRTH. EXCESS ENERGY INTAKE INDUCES HYPERTROPHY AND HYPERPLASIA OF ADIPOSE TISSUE WITH SUBSEQUENT DEVELOPMENT OF SYSTEMIC INSULIN RESISTANCE, WHICH IS ANOTHER IMPORTANT RISK FACTOR FOR NAFLD. DIET COMPOSITION AND IN PARTICULAR SIMPLE CARBOHYDRATE INTAKE (ESPECIALLY HIGH FRUCTOSE INTAKE) MAY PROMOTE THE DEVELOPMENT OF NAFLD, WHEREAS NON-DIGESTIBLE CARBOHYDRATES (DIETARY FIBER), BY AFFECTING GUT MICROBIOTA, MAY FAVOUR THE INTEGRITY OF GUT WALL AND REDUCE INFLAMMATION, OPPOSING THIS PROCESS. SATURATED FAT INTAKE MAY ALSO PROMOTE NAFLD DEVELOPMENT, WHEREAS UNSATURATED FAT INTAKE HAS SOME BENEFICIAL EFFECTS. PROTEIN INTAKE DOES NOT SEEM TO AFFECT THE DEVELOPMENT OF NAFLD, BUT FURTHER INVESTIGATION IS NEEDED. IN CONCLUSION, LIFESTYLE MODIFICATIONS TO INDUCE WEIGHT LOSS, THROUGH DIET AND PHYSICAL ACTIVITY, REMAIN THE MAINSTAY OF TREATMENT FOR PAEDIATRIC NAFLD. THE USE OF DIETARY SUPPLEMENTS, SUCH AS OMEGA-3 FATTY ACIDS AND PROBIOTICS, NEEDS FURTHER STUDY BEFORE RECOMMENDATION. 2022 19 4798 38 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 20 3707 38 INFLUENCE OF MATERNAL OVERNUTRITION AND GESTATIONAL DIABETES ON THE PROGRAMMING OF METABOLIC HEALTH OUTCOMES IN THE OFFSPRING: EXPERIMENTAL EVIDENCE. THE INCIDENCE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAVE RISEN ACROSS THE WORLD DURING THE PAST FEW DECADES AND HAS ALSO REACHED AN ALARMING LEVEL AMONG CHILDREN. IN ADDITION, WOMEN ARE CURRENTLY MORE LIKELY THAN EVER TO ENTER PREGNANCY OBESE. AS A RESULT, THE INCIDENCE OF GESTATIONAL DIABETES MELLITUS IS ALSO ON THE RISE. WHILE DIET AND LIFESTYLE CONTRIBUTE TO THESE TRENDS, POPULATION HEALTH DATA SHOW THAT MATERNAL OBESITY AND DIABETES DURING PREGNANCY DURING CRITICAL STAGES OF DEVELOPMENT ARE MAJOR FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC DISEASE IN ADOLESCENT AND ADULT OFFSPRING. FETAL PROGRAMMING OF METABOLIC FUNCTION, THROUGH PHYSIOLOGICAL AND (OR) EPIGENETIC MECHANISMS, MAY ALSO HAVE AN INTERGENERATIONAL EFFECT, AND AS A RESULT MAY PERPETUATE METABOLIC DISORDERS IN THE NEXT GENERATION. IN THIS REVIEW, WE SUMMARIZE THE EXISTING LITERATURE THAT CHARACTERIZES HOW MATERNAL OBESITY AND GESTATIONAL DIABETES MELLITUS CONTRIBUTE TO METABOLIC AND CARDIOVASCULAR DISORDERS IN THE OFFSPRING. IN PARTICULAR, WE FOCUS ON ANIMAL STUDIES THAT INVESTIGATE THE MOLECULAR MECHANISMS THAT ARE PROGRAMMED BY THE GESTATIONAL ENVIRONMENT AND LEAD TO DISEASE PHENOTYPES IN THE OFFSPRING. WE ALSO REVIEW INTERVENTIONAL STUDIES THAT PREVENT DISEASE WITH A DEVELOPMENTAL ORIGIN IN THE OFFSPRING. 2015