Z Geburtshilfe Neonatol 2009; 213 - FV_N_09_04
DOI: 10.1055/s-0029-1222820

Acquired hypermethylation of the hypothalamic insulin receptor promoter in neonatally overfed rats

T Harder 1, K Roepke 1, T Ziska 1, A Harder 2, JW Dudenhausen 3, A Plagemann 1
  • 1Klinik für Geburtsmedizin, "Experimentelle Geburtsmedizin", Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin
  • 2Institut für Neuropathologie, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin
  • 3Klinik für Geburtsmedizin, Charité Campus Virchow-Klinikum, Berlin, Berlin

Neonatal overnutrition leads to an increased risk of obesity and diabetes later in life (1). Rats overnourished neonatally by rearing in small litters develop permanent obesity disposition, which is accompanied by diabetogenic and cardiovascular alterations in terms of the metabolic syndrome (2). These animals show a neonatally “programmed“ hypothalamic insulin resistance with permanent hyperphagia (2, 3). Epigenomic mechanisms, like DNA methylation, might be responsible for processes of perinatal programming. We therefore investigated whether neonatal overnutrition leads to alterations of the DNA methylation pattern of the promoter of the insulin receptor gene. Neonatal overnutrition was induced by raising Wistar rats in small litters (3 pups per nest; SL) from day 3–21 of life. We investigated the hypothalamic DNA methylation pattern of a 615 bp fragment of the insulin receptor promoter, using bisulfite modification, cloning and sequencing. Although less than 1% of CpG dinucleotides of both groups were methylated, significant group differences were found within the 322 bp CpG island of the promoter. The proportion of animals which showed at least one methylated CpG was significantly increased in the SL group (p=0.04). Simultaneously, the percentage of methylated CpGs within the CpG island was higher in SL rats (p=0.01). For the first time, these data show that overnutrition during a critical developmental period can alter the DNA methylation pattern of a central nervous gene promoter. Alterations might predispose to decreased hypothalamic receptor expression and insulin sensing as causal factor for hyperphagia and perinatally programmed obesity disposition (4).

Literatur: (1) Plagemann, J. Perinat. Med. 2006; 34: 256-257. (2) Plagemann et al., Brain Res. 1999; 836: 146-155. (3) Davidowa & Plagemann, Neuroreport 2007; 18: 521-524. (4) Supported by the DFG (PL 241/4-1; GRK 1208)

Epigenetik - Perinatale Programmierung - Neonatalernährung - Übergewicht