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Background  Maternal metabolic insults as well as Gestational Diabetes Mellitus (GDM) influence the fetal health and may affect ‘offspring’s susceptibility to chronic diseases  via  epigenetic modifications. GDM, the most common metabolic disorder in pregnancy, can be considered the result of complex interactions between genetic and environmental factors. A critical point in this view is the identification of genes which are epigenetically modified under the influence of GDM. The melanocortin 4 receptor ( MC4R)  gene plays a crucial role in nutritional health by suppressing appetite and participating in energy control regulation. The correlations between pregnant ‘women’s metabolic profiles and placental epigenetic modifications of this gene have been poorly investigated.    Objective  The aim of this study was to evaluate the effect of GDM and maternal clinical parameters at the third trimester of pregnancy to DNA methylation levels in the placenta at CpG sites of  MC4R  gene.    Design and Methods  Socio-demographic and clinical characteristics, Mediterranean diet adherence, smoking habits, and physical activity were assessed at the third trimester of pregnancy of 60 Caucasian pregnant women, of which 33 with GDM. Clinical parameters of the newborns were recorded at birth.  MC4R  DNA methylation on maternal and fetal sides of the placenta was analyzed using bisulfite pyrosequencing.    Results   MC4R  DNA methylation levels at CpG1 and CpG2 were lower on the fetal side of the placenta in GDM-affected women than in non-GDM-affected recruits ( p  = 0.033). Moreover, DNA methylation levels on the maternal side at CpG1 were positively related to glucose concentration at 2-h oral glucose tolerance test (OGTT). On the other hand, CpG2 DNA methylation was positively related to both 1-h and 2-h during OGTT. Maternal DNA methylation level at CpG2 was also associated with low density lipoprotein cholesterol (LDL-C) at the third trimester of pregnancy (rho = 0.340,  p  &amp;lt; 0.05), while CpG1 methylation was negatively related to maternal weight variations at delivery (rho = −0.316,  p  &amp;lt; 0.05). Significant associations between  MC4R  DNA methylation on the maternal side and lipid profile at third trimester of pregnancy in women smokers were found.    Conclusion  Our results suggest that  MC4R  methylation profile in the placenta is related to maternal metabolic and nutritional conditions, potentially affecting fetal programming and the future metabolic health of the newborn.

The Obesogenic Environment: Epigenetic Modifications in Placental Melanocortin 4 Receptor Gene Connected to Gestational Diabetes and Smoking