Epigenetic mechanisms in the early life programming of obesity

Abstract

Obesity presents a major public health burden with prevalence rising in both children and adults. This disorder is associated with many adverse health outcomes and improved understanding of the mechanisms is required to develop effective preventive and treatment strategies. It has been hypothesised that environmental exposures such as poor nutrition in utero and during the early post natal period can programme an individual to develop obesity in later life. These early life exposures can be ‘memorised’ by the cell in the form of epigenetic modifications, changes to the biochemical structure and function of DNA. Such modifications include DNA methylation, the addition of a methyl group to cytosine residues which is involved in the regulation of gene transcription. Epigenetic mechanisms therefore represent an attractive mechanism to explain developmental programming phenomena. The overarching aim of this study was to establish the mediating role of epigenetic processes in linking modifiable environmental exposures with subsequent risk of obesity. This was addressed through interrogation of animal models, through the development and application of bioinformatic approaches and through epidemiological investigation of human population studies. Tissue level DNA methylation patterns were investigated in hypothalamus using immunohistochemical staining. No significant differences were discernible between methylation levels in the hypothalami of control rodents when compared to hypothalami from rodents that had been exposed in utero to a dietary regimen that induces metabolic perturbation and obesity in offspring. Bioinformatic approaches were used to develop and apply an in silico workflow to interrogate gene expression dataset, in this instance from a rodent model of dietary manipulation in utero and early postnatal life. The purpose of this in silico interrogation was to identify loci that were strong candidates for epigenetic regulation of gene expression. Four genes, Esr1, Fxn, Igf2r and Rbl2 were identified and the levels of promoter methylation at these loci were assessed in rodent liver tissue from offspring of exposed and unexposed mothers using pyrosequencing. DNA methylation levels in Igf2r were observed to be higher in animals exposed to a maternal obesogenic diet.