Review Epigenetic changes in the hypothalamic pro-opiomelanocortin gene: A mechanism linking maternal undernutrition to obesity in the offspring? Adam Stevens b,1 , Ghazala Begum a,1 , Anne White a,b, ⁎ a Faculty of Life Sciences, University of Manchester, UK b Faculty of Medical and Human Sciences, University of Manchester, UK abstract article info Article history: Received 9 August 2010 Received in revised form 6 October 2010 Accepted 29 October 2010 Available online xxxx Keywords: POMC Hypothalamus Glucocorticoid receptor Maternal undernutrition Programming Epigenetics 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. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. Programming of food intake and energy balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1. Neuropeptide regulation of food intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.2. Regulation of POMC expression in the hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.3. The role of POMC in food intake and energy balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3. Adverse maternal nutrition programs hypothalamic feeding centres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.1. Programming of hypothalamic neuropeptides with maternal undernutrition in the rat . . . . . . . . . . . . . . . . . . . . . . . . 0 3.2. Effects of maternal undernutrition on foetal programming in sheep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.3. Effects of maternal overnutrition on programming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4. Epigenetic effects on hypothalamic POMC pathways regulating food intake and energy balance . . . . . . . . . . . . . . . . . . . . . . . 0 4.1. Epigenetic changes in the foetus associated with maternal undernutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.2. Epigenetic changes in POMC after maternal overnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.3. Modulation of hypothalamic POMC as a result of epigenetic changes in the glucocorticoid receptor . . . . . . . . . . . . . . . . . . 0 5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 European Journal of Pharmacology xxx (2011) xxx–xxx ⁎ Corresponding author. Faculties of Life Sciences and Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK. Tel.: +44 161 275 5178, +44 161 275 5180 (Secretary). E-mail address: anne.white@manchester.ac.uk (A. White). 1 These authors contributed equally to this work. EJP-67065; No of Pages 8 0014-2999/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2010.10.111 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Please cite this article as: Stevens, A., et al., Epigenetic changes in the hypothalamic pro-opiomelanocortin gene: A mechanism linking maternal undernutrition to obesity in the offspring? Eur. J. Pharmacol. (2011), doi:10.1016/j.ejphar.2010.10.111