title: Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome.
abstract: Pre- and neonatal overfeeding programmes a permanent obesity disposition and accompanying diabetic and cardiovascular disorders, by unknown mechanisms. We proposed that early overfeeding may alter DNA methylation patterns of hypothalamic promoter regions of genes critically involved in the lifelong regulation of food intake and body weight. We induced neonatal overfeeding by rearing Wistar rats in small litters (SL) and thereafter mapped the DNA methylation status of CpG dinucleotides of gene promoters from hypothalamic tissue, using bisulfite sequencing. Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e. obesity, hyperleptinaemia, hyperglycaemia, hyperinsulinaemia, and an increased insulin/glucose ratio. Accompanying, without group difference to controls, the promoter of the main orexigenic neurohormone, neuropeptide Y, was methylated at low levels (i.e. < 5%). In contrast, in SL rats the hypothalamic gene promoter of the main anorexigenic neurohormone, proopiomelanocortin (POMC), showed hypermethylation (P < 0.05) of CpG dinucleotides within the two Sp1-related binding sequences (Sp1, NF-kappaB) which are essential for the mediation of leptin and insulin effects on POMC expression. Consequently, POMC expression lacked upregulation, despite hyperleptinaemia and hyperinsulinaemia. Accordingly, the extent of DNA methylation within Sp1-related binding sequences was inversely correlated to the quotients of POMC expression/leptin (P = 0.02) and POMC expression/insulin (P < 0.001), indicating functionality of acquired epigenomic alterations. These data for the first time demonstrate a nutritionally acquired alteration of the methylation pattern and, consequently, the regulatory 'set point' of a gene promoter that is critical for body weight regulation. Our findings reveal overfeeding as an epigenetic risk factor of obesity programming and consecutive diabetic and cardiovascular disorders and diseases, in terms of the metabolic syndrome.
authors.affiliation: Clinic of Obstetrics, Research Group Experimental Obstetrics, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany. andreas.plagemann@charite.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Plagemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Harder
authors.forename: Matthias
authors.initials: M
authors.lastname: Brunn
authors.forename: Anja
authors.initials: A
authors.lastname: Harder
authors.forename: Katharina
authors.initials: K
authors.lastname: Roepke
authors.forename: Manon
authors.initials: M
authors.lastname: Wittrock-Staar
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziska
authors.forename: Karen
authors.initials: K
authors.lastname: Schellong
authors.forename: Elke
authors.initials: E
authors.lastname: Rodekamp
authors.forename: Kerstin
authors.initials: K
authors.lastname: Melchior
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Dudenhausen
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D006963:Hyperphagia / Q000235:genetics* / Q000378:metabolism; D007031:Hypothalamus / Q000502:physiology; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin; D004247:DNA