title: Hypermethylation of Sp1 binding site suppresses hypothalamic POMC in neonates and may contribute to metabolic disorders in adults: impact of maternal dietary CLAs.
abstract: Epigenetic regulation of neuropeptide genes associated with central appetite control plays an important part in the development of nutritional programming. While proopiomelanocortin (POMC) is critical in appetite control, the molecular mechanism of methylation-related regulation of POMC remains unclear. Based on the report that the proximal specificity protein 1 (Sp1) binding site in POMC promoter is crucial for the leptin-mediated activation of POMC, the methylation of this site was investigated in this study in both cultured cells and postnatal mice reared by the dams with dietary supplementation of conjugated linoleic acids (CLAs). The change of milk composition made the offspring undergo the increase of food intake, suppression of POMC, attenuation of Sp1-promoter interaction, and the hypermethylation of cytosine guanine (CpG) dinucleotides at -100 and -103 within the Sp1 binding site of POMC promoter, which may be associated with the decrease of hypothalamic Sp1 and/or plasma S-adenosylhomocystein. In cultured cells, the methylation of the -100 CpG dinucleotides of the POMC promoter blocked both the formation of Sp1-promoter complex and the leptin-induced activation of POMC. In addition, a catch-up growth and adult metabolic changes like adult hyperglycemia and insulin resistance were observed in these postnatal pups, suggesting that this CLA-mediated hypermethylation may contribute, at least in part, to the metabolic disorders.
authors.affiliation: Laboratory of Animal Gene Engineering, College of Life Sciences, Henan Agricultural University, Zhengzhou, People's Republic of China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Ran
authors.initials: R
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.forename: Demin
authors.initials: D
authors.lastname: Cai
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Qu
authors.forename: Huihua
authors.initials: H
authors.lastname: Han
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Linfeng
authors.initials: L
authors.lastname: Wang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yao
authors.forename: Guoqing
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002478:Cells, Cultured; D019175:DNA Methylation; D019587:Dietary Supplements; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000032:analysis; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000032:analysis; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D051379:Mice; D008892:Milk / Q000737:chemistry; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D020738:Leptin; D044243:Linoleic Acids, Conjugated; D016329:Sp1 Transcription Factor; D011333:Pro-Opiomelanocortin; D005947:Glucose