Epigenetic changes in the hypothalamic pro-opiomelanocortin gene: A mechanism linking maternal undernutrition to obesity in the offspring?

Maternal undernutrition is associated with programming of obesity in offspring. While previous evidence has linked programming to the hypothalamic, pituitary, and adrenal (HPA) axis it could also affect the hypothalamic neuropeptides which regulate food intake and energy balance. Alpha melanocyte stimulating hormone (αMSH), a key regulator of these neuronal pathways, is derived from pro-opiomelanocortin (POMC) which is therefore a prime target for the programming of obesity. Several models of maternal undernutrition have identified changes in POMC in hypothalami from foetuses or offspring at various ages. These models have also shown that the offspring go on to develop obesity and/or glucose intolerance. It is our hypothesis that programming leads to epigenetic changes in hypothalamic neuropeptide genes. Therefore when there is subsequent increased food availability, the epigenetic changes could cause dysfunctional transcriptional regulation of energy balance. We present evidence of epigenetic changes in the POMC gene promoter in foetal hypothalami after peri-conceptional undernutrition. In this model there are also epigenetic changes in the hypothalamic glucocorticoid receptor with consequent up-regulation of the receptor which could lead to alterations in the regulation of POMC and neuropeptide Y (NPY) in the hypothalamus. Thus maternal undernutrition could cause epigenetic changes in the POMC and glucocorticoid receptor genes, in the foetal hypothalamus, which may predispose the offspring to altered regulation of food intake, energy expenditure and glucose homeostasis, later in life.