Table 1.

Association of maternal obesity with offspring metabolic diseases based on the role of DNA modification in various studies.

Diseases	Major Finding	Reference
Non-alcoholic fatty liver disease (NAFLD)	Maternal obesity and maternal overnutrition are associated with Leptin hypermethylation and peroxisome proliferator-activated receptor (PPAR)α hypomethylation in the tissue of offspring’s oocytes and liver	[54,55]
	PPARG and liver X receptor α(LXRα) which are involved in the metabolism of several important lipids, are significantly hypermethylated in the liver tissues of mice offspring born to obese mothers	[56,57]
	Lipin 1, a gene involved in lipid generation, was hypermethylated in the transcription factor binding sites of the offspring’s liver tissue as a result of maternal obesity	[58]
	DNA methylation levels in the promoters of the glycerol-3-phosphate acyltransferase 1 (GPAT1) is lower and the transcriptome level of GPAT1 and sterol regulatory element binding protein-1 (SREBP-1) are higher in the offspring of obese mothers compared to offspring of normal weight mothers, in association with increased hepatic triglyceride levels	[59,60]
	Offspring exposure to maternal obesity and maternal overnutrition also induced glucose-regulated protein (GRP)-78 hypermethylation in association with downregulation of gene expression mothers	[61]
	Platelet-derived growth factor receptor (PDGFR)-β, a proinflammatory and profibrogenic regulator, which can act as a potential target in diagnosing and treating early stages of non-alcoholic fatty liver disease (NAFLD) fibrosis, was hypomethylated and upregulated transcriptionally in the offspring of obese mothers	[62]
Obesity	Exposure to maternal overnutrition or maternal obesity before or during gestation or lactation, leads to an incremental increase in the mRNA level of several adipogenic genes in in perirenal fat in fetal sheep. The offspring such as PPARG, fatty acid synthase, lipoprotein lipase, adiponectin, and leptin which participate in energy and lipid metabolism. Alteration is the DNA methylation of those genes was also demonstrated in the in visceral fat of mice offspring due to maternal obesity	[63,64]
	Studies on rodents have revealed that maternal obesity leads to increased birth weight, increased leptin levels, and hypermethylation of pro-opiomelanocortin (POMC) in the promoter regions of the offspring, which has a vital role in leptin resistance	[65,66]
	Previous studies also observed that maternal obesity may influence the offspring’s metabolism and increased the prevalence of offspring obesity, and this could be affected by the promoter DNA methylation of three key genes related with metabolic syndrome (PPARGC1A, PPARG, and mitochondrial transcription factor A (TFAM)) in umbilical cord blood	[52,67]
	Offspring born to obese mothers have decreased gene methylation of key adipogenic transcription regulators of adipogenesis, including CCAAT/enhancer binding protein beta (C/EBP-β) and zinc-finger proteins, which may result in elevated adipogenic tissue differentiation during embryonic and fetal growth periods and result in metabolic disorders	[68,69]
	DNA methylation array demonstrated that genes related to fatty acid oxidation (Protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2), acetyl-CoA carboxylase 2 (ACC2), carnitine palmitoiltransferase I (CPT1A), succinate dehydrogenase subunit C (SDHC)) were hypermethylated in the cord blood mesenchymal stem cells (MSCs) of obese mothers, which was positively associated with infant adiposity	[70]
	TAP-binding protein (TAPBP) is hypermethylated in umbilical cord blood of obese mothers, which suggests that maternal obesity can result in the development of obesity in the offspring via reducing tapasin (decreased tapasin can lower CD8 + T-cell responses in vitro) leading to impaired immune responses in offspring	[71,72]
	Aryl hydrocarbon receptor repressor (AhRR) was hypermethylated in the umbilical cord of obese mothers compared to lean mothers. AhRR functions as an inhibitor of adipocyte differentiation by negatively regulating PPARG during adipogenesis. Collectively, these data suggest that offspring of obese mothers are at increased risk of obesity and metabolic disease	[73,74,75]
Diabetes	Different genes are involved in type 1 or type 2 diabetes mellitus, such as human leukocyte antigen (HLA)-DQA1, HLA-DQB1, POMC, insulin-like growth factor 2 (IGF2), insulin receptor (INSR), fat mass-and obesity-associated protein (FTO) as well as tumor necrosis factor (TNF), are either hypermethylated (HLA-DQA1, HLA-DQB1, POMC, IGF2, and INSR) or hypomethylated (FTO and TNF) in the promoter region of whole blood sample from offspring born after maternal bariatric surgery compared to before bariatric surgery	[76,77]
	Genes involved in immunological processes (including TNF-α, interleukin, major histocompatibility complex (MHC) class I and II signaling pathways) were differentially methylated in offspring of obese mothers.	[78,79]
	Several genes involved in immune response in patients with type 1 diabetes were hypermethylated in umbilical cord blood-derived monocytes, including signal transducer and activator of transcription 1 (STAT1), T cell receptors (CD247, CD28, and CD3E), MHC I class or II subunits (HLADMB and HLA-DQB1)	[79]
	Leptin promoters were hypermethylated in the placentas of obese mothers leading to decreased placental leptin expression while leptin deficiency is associated with hyperglycemia both in humans and animals	[80,81,82]
Chronic kidney disease (CKD)	Incremental increase in oxidative stress and mitochondrial impairment during the period of oocyte development laid down through epigenetic changes can also contribute to the transgenerational development of maternal obesity related CKD	[47,83]
	Maternal obesity correlates with global hypomethylation of key immune genes (T cells, cytokine, and chemokines) in umbilical cord blood-derived monocytes, such of which are involved in the development of inflammatory responses in kidney tissues and CKD pathology	[79]