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Licensed Unlicensed Requires Authentication Published by De Gruyter May 5, 2010

Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding

  • Andreas Plagemann , Katharina Roepke , Thomas Harder , Matthias Brunn , Anja Harder , Manon Wittrock-Staar , Thomas Ziska , Karen Schellong , Elke Rodekamp , Kerstin Melchior and Joachim W. Dudenhausen
From the journal


Aim: Prenatal and neonatal overfeeding programs a permanent obesity and diabetes disposition, e.g., due to induction of hypothalamic insulin resistance. We investigated acquired alterations of the DNA methylation pattern of the hypothalamic insulin receptor promoter (IRP) which might be an underlying molecular mechanism.

Methods: Neonatal overfeeding was induced by rearing Wistar rats in small litters (SL). Methylation of CpG-dinucleotides of the hypothalamic IRP was mapped using bisulfite sequencing.

Results: Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperglycemia, hyperinsulinemia, and increased insulin/glucose-ratio. The proportion of animals carrying any methylated CpG residue in the 322 bp CpG island of the IRP was increased in neonatally overfed SL rats (n=8), as compared to controls (n=8; P=0.04). Moreover, the mean percentage of methylated CpG positions was also higher in SL rats (P=0.01). Over both groups, neonatal blood glucose levels were positively correlated to the extent of promoter methylation (r=0.52; P=0.04).

Conclusions: This study characterizes for the first time the IRP epigenomically in any species and tissue. Our data reveal that the IRP is vulnerable to hypermethylation due to overnutrition, probably especially glucose-dependent in a dose-response manner. This paradigmatically indicates the impact of nutrient-dependent epigenetic malprogramming, leading to a “diabesity” disposition which may become pathogenic throughout life.

Corresponding author: Prof. A. Plagemann, MD Head of “Experimental Obstetrics” Clinic of Obstetrics Charité – University Medicine Berlin Campus Virchow-Klinikum Berlin Germany Tel.: +49-(0) 30-450 52 40 41 Fax: +49-(0) 30-450 52 49 28

Received: 2009-8-5
Revised: 2009-11-2
Accepted: 2009-12-15
Published Online: 2010-05-05
Published Online: 2010-05-5
Published in Print: 2010-07-01

©2010 by Walter de Gruyter Berlin New York

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