Dilemma of Epigenetic Changes Causing or Reducing Metabolic Disorders in Offsprings of Obese Mothers

Abstract

Maternal obesity is associated with fetal complications predisposing later to the development of metabolic syndrome during childhood and adult stages. High-fat diet seems to influence individuals and their subsequent generations in mediating weight gain, insulin resistance, obesity, high cholesterol, diabetes, and cardiovascular disorder. Research evidence strongly suggests that epigenetic alteration is the major contributor to the development of metabolic syndrome through DNA methylation, histone modifications, and microRNA expression. In this review, we have discussed the outcome of recent studies on the adverse and beneficial effects of nutrients and vitamins through epigenetics during pregnancy. We have further discussed about the miRNAs altered during maternal obesity. Identification of new epigenetic modifiers such as mesenchymal stem cells condition media (MSCs-CM)/exosomes for accelerating the reversal of epigenetic abnormalities for the development of new treatments is yet another aspect of the present review.

Key words

maternal obesity - MSCs secretome - epigenetic modification - epigenetic modifier - nutrition, metabolic syndrome

Publication History

Received: 20 January 2023

Accepted after revision: 15 August 2023

Article published online:
09 October 2023

• References

• 1 World Health Organization. Noncommunicable diseases progress monitor 2022. World Health Organization; Geneva, Switzerland: 2022
• 2 Simmons RK, Alberti KG, Gale EA. et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO expert consultation. Diabetologia 2010; 53: 600-605
• 3 Barker DJ, Osmond C. Low birth weight and hypertension. BMJ 1988; 297: 134-135
• 4 Barker DJP, Osmond C, Winter PD. et al. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 334: 577-580
• 5 Sales VM, Ferguson-Smith AC, Patti ME. Epigenetic mechanisms of transmission of metabolic disease across generations. Cell Metab 2017; 25: 559-571
• 6 Laker RC, Wlodek ME, Connelly JJ. et al. Epigenetic origins of metabolic disease: the impact of the maternal condition to the offspring epigenome and later health consequences. Food Sci Hum Wellness 2013; 2: 1-11
• 7 Ramirez-Alarcon K, Sanchez-Agurto A, Lamperti L. et al. Epigenetics, maternal diet and metabolic programming. Open Biol J 2019; 7: 45-51
• 8 Yang H, Chen N, Fan L. et al. Pre-weaning exposure to maternal high-fat diet is a critical developmental window for programming the metabolic system of offspring in mice. Front Endocrinol (Lausanne) 2022; 13: 816107
• 9 Zhang Q, Xiao X, Zheng J. et al. A maternal high-fat diet induces DNA methylation changes that contribute to glucose intolerance in offspring. Front Endocrinol (Lausanne) 2019; 10: 871
• 10 Zhang Q, Xiao X, Zheng J. et al. Maternal high-fat diet disturbs the DNA methylation profile in the brown adipose tissue of offspring mice. Front Endocrinol (Lausanne) 2021; 12: 705827
• 11 Peng H, Xu H, Wu J. et al. Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease. Liver Int 2021; 41: 1305-1319
• 12 Peng H, Li J, Xu H. et al. Offspring NAFLD liver phospholipid profiles are differentially programmed by maternal high-fat diet and maternal one carbon supplement. J Nutr Biochem 2023; 111: 109187
• 13 Keleher MR, Zaidi R, Shah S. et al. Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS One 2018; 13: e0192606
• 14 Penn A, McPherson N, Fullston T. et al. Maternal high-fat diet changes DNA methylation in the early embryo by disrupting the TCA cycle intermediary alpha ketoglutarate. Reproduction 2023; 165: 347-362
• 15 Aagaard-Tillery KM, Grove K, Bishop J. et al. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 2008; 41: 91-102
• 16 Esler WP, Bence KK. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol Gastroenterol Hepatol 2019; 8: 247-267
• 17 Blin G, Liand M, Mauduit C. et al. Maternal exposure to high-fat diet induces long-term derepressive chromatin marks in the heart. Nutrients 2020; 12: 181
• 18 Suter MA, Chen A, Burdine MS. et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J 2012; 26: 5106-5114
• 19 Moody L, Chen H, Pan YX. Postnatal diet remodels hepatic DNA methylation in metabolic pathways established by a maternal high-fat diet. Epigenomics 2017; 9: 1387-1402
• 20 Masuyama H, Mitsui T, Nobumoto E. et al. The effects of high-fat exposure in utero on the obesogenic and diabetogenic traits through epigenetic changes in adiponectin and leptin gene expression for multiple generations in female mice. Endocrinology 2015; 156: 2482-2491
• 21 Masuyama H, Mitsui T, Eguchi T. et al. The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters. Am J Physiol Endocrinol Metab 2016; 311: E236-E245
• 22 Marco A, Kisliouk T, Tabachnik T. et al. DNA CpG methylation (5-methylcytosine) and its derivative (5-hydroxymethylcytosine) alter histone posttranslational modifications at the pomc promoter, affecting the impact of perinatal diet on leanness and obesity of the offspring. Diabetes 2016; 65: 2258-2267
• 23 Marco A, Kisliouk T, Tabachnik T. et al. Overweight and CpG methylation of the Pomc promoter in offspring of high-fat-diet-fed dams are not “reprogrammed” by regular chow diet in rats. FASEB J 2014; 28: 4148-4157
• 24 Ou XH, Zhu CC, Sun SC. Effects of obesity and diabetes on the epigenetic modification of mammalian gametes. J Cell Physiol 2019; 234: 7847-7855
• 25 Dalfrà MG, Burlina S, Del Vescovo GG. et al. Genetics and epigenetics: new insight on gestational diabetes mellitus. Front Endocrinol (Lausanne) 2020; 11: 602477
• 26 Sinha N, Lydia Walker G, Sen A. Looking at the future through the mother’s womb: gestational diabetes and offspring fertility. Endocrinology 2021; 162: bqab209
• 27 Franzago M, Porreca A, D’Ardes M. et al. The obesogenic environment: epigenetic modifications in placental melanocortin 4 receptor gene connected to gestational diabetes and smoking. Front Nutr 2022; 9: 879526
• 28 Nogues P, Dos Santos E, Jammes H. et al. Maternal obesity influences expression and DNA methylation of the adiponectin and leptin systems in human third-trimester placenta. Clin Epigenetics 2019; 11: 20
• 29 Alba-Linares JJ, Pérez RF, Tejedor JR. et al. Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways. Cardiovasc Diabetol 2023; 22: 44
• 30 Li T, Chen K, Liu G. et al. Calorie restriction prevents the development of insulin resistance and impaired lipid metabolism in gestational diabetes offspring. Pediatr Res 2017; 81: 663-671
• 31 Hernandez-Saavedra D, Moody L, Xu GB. et al. Epigenetic regulation of metabolism and inflammation by calorie restriction. Advances in nutrition (Bethesda, Md) 2019; 10: 520-536
• 32 Garcia-Segura L, Abreu-Goodger C, Hernandez-Mendoza A. et al. High-throughput profiling of caenorhabditis elegans starvation-responsive microRNAs. PLoS One 2015; 10: e0142262
• 33 Unnikrishnan A, Jackson J, Matyi SA. et al. Role of DNA methylation in the dietary restriction mediated cellular memory. Geroscience 2017; 39: 331-345
• 34 Miyoshi M, Saito K, Jia H. et al. Maternal protein restriction and post-weaning high-fat feeding alter plasma amino acid profiles and hepatic gene expression in mice offspring. Foods 2022; 11: 753
• 35 Ong TP, Ozanne SE. Developmental programming of type 2 diabetes: Early nutrition and epigenetic mechanisms. CurrOpin Clin NutrMetab Care 2015; 18: 354-360
• 36 Persico G, Casciaro F, Marinelli A. et al. Comparative analysis of histone H3K4me3 distribution in mouse liver in different diets reveals the epigenetic efficacy of cyanidin-3-O-glucoside dietary intake. Int J Mol Sci 2021; 22: 6503
• 37 LaBarre JL, McCabe CF, Jones TR. et al. Maternal lipodome across pregnancy is associated with the neonatal DNA methylome. Epigenomics 2020; 12: 2077-2092
• 38 Tindula G, Lee D, Huen K. et al. Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort. Environ Epigenet 2019; 5: dvz004
• 39 Ouidir M, Zeng X, Workalemahu T. et al. Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases. Epigenomics 2020; 12: 921-934
• 40 Guay SP, Houde AA, Breton E. et al. DNA methylation at LRP1 gene locus mediates the association between maternal total cholesterol changes in pregnancy and cord blood leptin levels. J Dev Orig Health Dis 2020; 11: 369-378
• 41 de la Rocha C, Rodríguez-Ríos D, Ramírez-Chávez E. et al. Cumulative metabolic and epigenetic effects of paternal and/or maternal supplementation with arachidonic acid across three consecutive generations in mice. Cells 2022; 11: 1057
• 42 Rudolph MC, Jackman MR, Presby DM. et al. Low neonatal plasma n-6/n-3 PUFA ratios regulate offspring adipogenic potential and condition adult obesity resistance. Diabetes 2018; 67: 651-661
• 43 Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab 2017; 25: 27-42
• 44 LeBlanc JG, Milani C, de Giori GS. et al. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. CurrOpinBiotechnol 2013; 24: 160-168
• 45 Kumar KA, Lalitha A, Pavithra D. et al. Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. J NutrBiochem 2012; 24: 25-31
• 46 Yajnik CS, Deshpande SS, Jackson AA. et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 2008; 51: 29-38
• 47 Mahajan A, Sapehia D, Thakur S. et al. Effect of imbalance in folate and vitamin B12 in maternal/parental diet on global methylation and regulatory miRNAs. Sci Rep 2019; 9: 17602
• 48 Mahajan A, Sapehia D, Bagga R. et al. Different dietary combinations of folic acid and vitamin B12 in parental diet results in epigenetic reprogramming of IGF2R and KCNQ1OT1 in placenta and fetal tissues in mice. Mol Reprod Dev 2021; 88: 437-458
• 49 Sinclair KD, Allegrucci C, Singh R. et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A 2007; 49: 19351-19356
• 50 Chen G, Broséus J, Hergalant S. et al. Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease. Mol Nutr Food Res 2015; 59: 293-302
• 51 Cho CE, Pannia E, Huot PS. et al. Methyl vitamins contribute to obesogenic effects of a high multivitamin gestational diet and epigenetic alterations in hypothalamic feeding pathways in Wistar rat offspring. Mol Nutr Food Res 2015; 59: 476-489
• 52 Guéant JL, Elakoum R, Ziegler O. et al Nutritional models of foetal programming and nutrigenomic and epigenomic dysregulations of fatty acid metabolism in the liver and heart. Pflugers Arch 2014; 466: 833-850
• 53 Park HJ, Bailey LB, Shade DC. et al. Distinctions in gene-specific changes in DNA methylation in response to folic acid supplementation between women with normal weight and obesity. Obes Res Clin Pract 2017; 11: 665-676
• 54 Yadav DK, Shrestha S, Lillycrop KA. et al. Vitamin B₁₂ supplementation influences methylation of genes associated with Type 2 diabetes and its intermediate traits. Epigenomics 2018; 10: 71-90
• 55 Cho CE, Sánchez-Hernández D, Reza-López SA. et al. High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 2013; 8: 710-719
• 56 Salonen MK, Wasenius N, Kajantie E. et al. Physical activity, body composition and metabolic syndrome in young adults. PLoS One 2015; 10: e0126737
• 57 Lee J, Kim Y, Jeon JY. Association between physical activity and the prevalence of metabolic syndrome: from the Korean National Health and Nutrition Examination Survey, 1999-2012. Springerplus 2016; 5: 1870
• 58 Grazioli E, Dimauro I, Mercatelli N. et al. Physical activity in the prevention of human diseases: role of epigenetic modifications. BMC Genomics 2017; 18: 802
• 59 Antoun E, Kitaba NT, Titcombe P. et al. UPBEAT Consortium. Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial. PLoS Med 2020; 17: e1003229
• 60 Kusuyama J, Alves-Wagner AB, Makarewicz NS. et al. Effects of maternal and paternal exercise on offspring metabolism. Nat Metab 2020; 2: 858-872
• 61 Kusuyama J, Makarewicz NS, Albertson BG. et al. Maternal exercise-induced SOD3 reverses the deleterious effects of maternal high-fat diet on offspring metabolism through stabilization of H3K4me3 and protection against WDR82 carbonylation. Diabetes 2022; 71: 1170-1181
• 62 Jönsson J, Renault KM, García-Calzón S. et al. Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring. Diabetes 2021; 70: 854-866
• 63 Claycombe-Larson KJ, Bundy A, Lance EB. et al. Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J mice. J Nutr Biochem 2022; 99: 108853
• 64 Kusuyama J, Makarewicz NS, Albertson BG. et al. Maternal exercise-induced SOD3 reverses the deleterious effects of maternal high-fat diet on offspring metabolism through stabilization of H3K4me3 and protection against WDR82 carbonylation. Diabetes 2022; 71: 1170-1181
• 65 Laker RC, Altıntaş A, Lillard TS. et al. Exercise during pregnancy mitigates negative effects of parental obesity on metabolic function in adult mouse offspring. J Appl Physiol 1985; 2021: 605-616
• 66 Laker RC, Lillard TS, Okutsu M. et al. Exercise prevents maternal high-fat diet-induced hypermethylation of the Pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes 2014; 63: 1605-1611
• 67 Axsom JE, Libonati JR. Impact of parental exercise on epigenetic modifications inherited by offspring: a systematic review. Physiol Rep 2019; 7: e14287
• 68 Son JS, Zhao L, Chen Y. et al. Maternal exercise via exerkine apelin enhances brown adipogenesis and prevents metabolic dysfunction in offspring mice. Sci Adv 2020; 6: eaaz0359
• 69 Philip S, Martin RV, van Donkelaar A. et al. Global chemical composition of ambient fine particulate matter for exposure assessment. Environ Sci Technol 2014; 48: 13060-13068
• 70 Reşitoğlu İA, Altinişik K, Keskin A. The pollutant emissions from diesel-engine vehicles and exhaust aftertreatment systems. Clean Technol Environ Policy 2015; 17: 15-27
• 71 Xing J, Mathur R, Pleim J. et al. Observations and modeling of air quality trends over 1990-2010 across the Northern Hemisphere: China, the United States and Europe. Atmospheric. Chem Phys 2015; 15: 2723-2747
• 72 Guarnieri M, Balmes JR. Outdoor air pollution and asthma. Lancet 2014; 383: 1581-1592
• 73 US EPA O. Ground-level ozone basics. US EPA. 2015 [cited 2019 Mar 18]
• 74 Hamanaka RB, Mutlu GM. Particulate matter air pollution: effects on the cardiovascular system. Front Endocrinol (Lausanne) 2018; 9: 680
• 75 Yang BY, Qian ZM, Li S. et al. Ambient air pollution in relation to diabetes and glucose-homoeostasis markers in China: a cross-sectional study with findings from the 33 communities Chinese health study. Lancet Planet Health 2018; 2: e64-e73
• 76 Rajagopalan S, Al-Kindi SG, Brook RD. Air Pollution and Cardiovascular Disease. J Am Coll Cardiol 2018; 72: 2054
• 77 Wei Y, Zhang JJ, Li Z. et al. Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing. FASEB J 2016; 30: 2115-2122
• 78 Starling AP, Wood C, Liu C. et al. Ambient air pollution during pregnancy and DNA methylation in umbilical cord blood, with potential mediation of associations with infant adiposity: The Healthy Start study. Environ Res 2022; 214: 113881
• 79 Kingsley SL, Eliot MN, Whitsel EA. et al. Maternal residential proximity to major roadways, birth weight, and placental DNA methylation. Environ Int 2016; 92–93: 43-49
• 80 Cai J, Zhao Y, Liu P. et al. Exposure to particulate air pollution during early pregnancy is associated with placental DNA methylation. Sci Total Environ 2017; 607–608: 1103-1108
• 81 Ohn M, Jaffe A, Selvadurai H. Persistent growth effects of inhaled corticosteroids. J Paediatr Child Health 2016; 52: 964-966
• 82 Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci 2016; 17: 1712
• 83 Kennedy EM, Hermetz K, Burt A. et al. Placental microRNAs relate to early childhood growth trajectories. Pediatr Res 2022; 94: 341-348
• 84 Dinesen S, El-Faitarouni A, Dalgaard LT. Circulating microRNAs associated with gestational diabetes mellitus: useful biomarkers?. J Endocrinol 2022; 256: e220170
• 85 Tryggestad JB, Vishwanath A, Jiang S. et al. Influence of gestational diabetes mellitus on human umbilical vein endothelial cell miRNA. Clin Sci (Lond) 2016; 130: 1955-1967
• 86 Shah KB, Chernausek SD, Teague AM. et al. Maternal diabetes alters microRNA expression in fetal exosomes, human umbilical vein endothelial cells and placenta. Pediatr Res 2021; 89: 1157-1163
• 87 Mandò C, Abati S, Anelli GM. et al. Epigenetic profiling in the saliva of obese pregnant women. Nutrients 2022; 14: 2122
• 88 Zhao H, Shen J, Daniel-MacDougall C, Wu X. et al. Plasma MicroRNA signature predicting weight gain among Mexican-American women. Obesity (Silver Spring) 2017; 25: 958-964
• 89 Simino LAP, Panzarin C, Fontana MF. et al. MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies. Sci Rep 2021; 11: 8980
• 90 Simino LAP, Fontana MF, de Fante T. et al. Hepatic epigenetic reprogramming after liver resection in offspring alleviates the effects of maternal obesity. Front Cell Dev Biol 2022; 10: 830009
• 91 Huang XY, Chen JX, Ren Y. et al. Exosomal miR-122 promotes adipogenesis and aggravates obesity through the VDR/SREBF1 axis. Obesity (Silver Spring) 2022; 30: 666-679
• 92 Zhong FY, Li J, Wang YM. et al. MicroRNA-506 modulates insulin resistance in human adipocytes by targeting S6K1 and altering the IRS1/PI3K/AKT insulin signaling pathway. J Bioenerg Biomembr 2021; 53: 679-692
• 93 Mennitti LV, Carpenter AAM, Loche E. et al. Effects of maternal diet-induced obesity on metabolic disorders and age-associated miRNA expression in the liver of male mouse offspring. Int J Obes (Lond) 2022; 46: 269-278
• 94 Zhou Y, Xia M, Cui C. et al. Circulating Exosomal miR-221 from Maternal Obesity Inhibits Angiogenesis via Targeting Angptl2 . Int J Mol Sci 2021; 22: 10343
• 95 Gaytán-Pacheco N, Lima-Rogel V, Méndez-Mancilla A. et al. Changes in PPAR-γ expression are associated with microRNA profiles during fetal programming due to maternal overweight and obesity. Gynecol Obstet Invest 2021; 86: 415-426
• 96 Sørensen AE, van Poppel MNM, Desoye G. et al. The DALI Core Investigator Group. The predictive value of miR-16, -29a and -134 for early identification of gestational diabetes: a nested analysis of the DALI cohort. Cells 2021; 10: 170
• 97 Yan X, Huang Y, Zhao JX. et al. Maternal obesity downregulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes 2013; 37: 568-575
• 98 Carreras-Badosa G, Bonmatí A, Ortega FJ. et al. Dysregulation of placental miRNA in maternal obesity is associated with pre- and postnatal growth. J Clin Endocrinol Metab 2017; 102: 2584-2594
• 99 Joshi A, Azuma R, Akumuo R. et al. Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus. Int J Obes (Lond) 2020; 44: 1497-1507
• 100 Carè A, Catalucci D, Felicetti F. et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med 2007; 13: 613-618
• 101 Lino CA, de Oliveira Silva T, Lunardon G. et al. Ablation of miRNA-22 protects against obesity-induced adipocyte senescence and ameliorates metabolic disorders in middle-aged mice. Mech Ageing Dev 2023; 11: 111775
• 102 Kuppusamy KT, Jones DC, Sperber H. et al. Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc Natl Acad Sci U S A 2015; 112: E2785-E2794
• 103 Porrello ER, Johnson BA, Aurora AB. et al. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res 2011; 109: 670-679
• 104 Kim J, Koo BK, Knoblich JA. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 2020; 21: 571-584
• 105 Baker PR, Patinkin Z, Shapiro AL. et al. Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism. JCI Insight 2017; 2: e94200
• 106 Sureshchandra S, Chan CN, Robino JJ. et al. Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques. Stem Cell Rep 2022; 17: 2595-2609
• 107 Hu X, An J, Ge Q. et al. Maternal high-fat diet reduces type-2 neural stem cells and promotes premature neuronal differentiation during early postnatal development. Nutrients 2022; 14: 2813
• 108 Boyle KE, Patinkin ZW, Shapiro AL. et al. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: The Healthy Start BabyBUMP Project. Diabetes 2016; 65: 647-659
• 109 Boyle KE, Patinkin ZW, Shapiro ALB. et al. Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants. Mol Metab 2017; 6: 1503-1516
• 110 Iaffaldano L, Nardelli C, D’Alessio F. et al. Altered bioenergetic profile in umbilical cord and amniotic mesenchymal stem cells from newborns of obese women. Stem Cells Dev 2018; 27: 199-206
• 111 Chaves AB, Zheng D, Johnson JA. et al. Infant mesenchymal stem cell insulin action is associated with maternal plasma free fatty acids, independent of obesity status: The Healthy Start Study. Diabetes 2022; 71: 1649-1659
• 112 Lopes A FC. Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes. Clin Epigenet 2020; 12: 182
• 113 Matilainen O, Quirós PM, Auwerx J. Mitochondria and epigenetics – crosstalk in homeostasis and stress. Trends Cell Biol 2017; 27: 453-463
• 114 Chen JR, Lazarenko OP, Zhao H. et al. Maternal obesity impairs skeletal development in adult offspring. J Endocrinol 2018; 239: 33-47
• 115 Fan W, Tang S, Fan X. et al. SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B. Elife 2021; 10: e67452
• 116 Chen JR, Lazarenko OP, Blackburn ML. et al. Maternal obesity programs senescence signaling and glucose metabolism in osteo-progenitors from rat and human endocrinology 2016; 157: 4172-4183
• 117 Rosales W, Lizcano F. The histone demethylase JMJD2A modulates the induction of hypertrophy markers in iPSC-derived cardiomyocytes. Front Genet 2018; 9: 14
• 118 Kelly AC, Powell TL, Jansson T. Placental function in maternal obesity. Clin Sci (Lond) 2020; 134: 961-984
• 119 Howell KR, Powell TL. Effects of maternal obesity on placental function and fetal development. Reproduction 2017; 153: R97-R108
• 120 Kotikalapudi N, Sampath SJP, Sinha SN. et al. Human placental mesenchymal stromal cell therapy restores the cytokine efflux and insulin signaling in the skeletal muscle of obesity-induced type 2 diabetes rat model. Hum Cell 2022; 35: 557-571
• 121 Lee CW, Hsiao WT, Lee OK. Mesenchymal stromal cell-based therapies reduce obesity and metabolic syndromes induced by a high-fat diet. Transl Res 2017; 182: 61-74.e8
• 122 Meng Y, Eirin A, Zhu XY. et al. Micro-RNAS regulate metabolic syndrome-induced senescence in porcine adipose tissue-derived mesenchymal stem cells through the P16/MAPK pathway. Cell Transplant 2018; 27: 1495-1503
• 123 Park WS, Ahn SY, Sung SI. et al. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res 2018; 83: 214-222
• 124 Xie CR, Sun H, Wang FQ. et al. Integrated analysis of gene expression and DNA methylation changes induced by hepatocyte growth factor in human hepatocytes. Mol Med Rep 2015; 12: 4250-4258
• 125 Fu W, Yue Y, Miao K. et al. Repression of FGF signaling is responsible for Dnmt3b inhibition and impaired de novo DNA methylation during early development of in vitro fertilized embryos. Int J Biol Sci 2020; 16: 3085-3099
• 126 Balakrishnan A, Guruprasad KP, Satyamoorthy K. et al. Interleukin-6 determines protein stabilization of DNA methyltransferases and alters DNA promoter methylation of genes associated with insulin signaling and angiogenesis. Lab Invest 2018; 98: 1143-1158
• 127 Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 2017; 35: 851-858
• 128 Kong H, Liu P, Li H. et al. Mesenchymal stem cell-derived extracellular vesicles: the novel therapeutic option for regenerative dentistry. Stem Cell Rev Rep 2023; 19: 46-58
• 129 Fullerton JL, Cosgrove CC, Rooney RA. et al. Extracellular vesicles and their microRNA cargo in ischaemic stroke. J Physiol 2022; DOI: 10.1113/JP282050.
• 130 Nakamura Y, Miyaki S, Ishitobi H. et al. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett 2015; 589: 1257-1265
• 131 Liang X, Zhang L, Wang S. et al. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 2016; 129: 2182-2189
• 132 Sharma S, Bhonde R. Genetic and epigenetic stability of stem cells: Epigenetic modifiers modulate the fate of mesenchymal stem cells. Genomics 2020; 112: 3615-3623