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

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  • POMCHypothalamusGlucocorticoid receptorMaternal undernutritionProgramming

    arget for the programming of obesity. Several models of maternal undernutrition

    . . .2. Programming of food intake and energy b

    European Journal of Pharmacology 660 (2011) 194201

    Contents lists available at ScienceDirect

    European Journal of Pharmacology2.3. The role of POMC in food intake and energy balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953. Adverse maternal nutrition programs hypothalamic feeding centres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

    3.1. Programming of hypothalamic neuropeptides with maternal undernutrition in the rat . . . . . . . . . . . . . . . . . . . . . . . . 1963.2. Effects of maternal undernutrition on foetal programming in sheep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1963.3. Effects of maternal overnutrition on programming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

    4. Epigenetic effects on hypothalamic POMC pathways regulating food intake and energy balance . . . . . . . . . . . . . . . . . . . . . . . 1964.1. Epigenetic changes in the foetus associated with maternal undernutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1974.2. Epigenetic changes in POMC after maternal overnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1974.3. Modulation of hypothalamic POMC as a result of epigenetic changes in the glucocorticoid receptor . . . . . . . . . . . . . . . . . . 197

    5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 Corresponding author. Faculties of Life Sciences anBuilding, Manchester M13 9PT, UK. Tel.: +44 161 275 5

    E-mail address: anne.white@manchester.ac.uk (A. W1 These authors contributed equally to this work.

    0014-2999/$ see front matter. Crown Copyright 20doi:10.1016/j.ejphar.2010.10.111alance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195take . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195the hypothalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1952.1. Neuropeptide regulation of food in2.2. Regulation of POMC expression inEpigenetics

    Contents

    1. Introduction . . . . . . . . . .have also shown that the offspring go on to develop obesity and/or glucose intolerance. It is our hypothesisthat programming leads to epigenetic changes in hypothalamic neuropeptide genes. Therefore when there issubsequent increased food availability, the epigenetic changes could cause dysfunctional transcriptionalregulation of energy balance. We present evidence of epigenetic changes in the POMC gene promoter in foetalhypothalami after peri-conceptional undernutrition. In this model there are also epigenetic changes in thehypothalamic glucocorticoid receptor with consequent up-regulation of the receptor which could lead toalterations in the regulation of POMC and neuropeptide Y (NPY) in the hypothalamus. Thus maternalundernutrition could cause epigenetic changes in the POMC and glucocorticoid receptor genes, in the foetalhypothalamus, which may predispose the offspring to altered regulation of food intake, energy expenditureand glucose homeostasis, later in life.

    Crown Copyright 2011 Published by Elsevier B.V. All rights reserved.

    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Keywords: have identied changes in POMC in hypothalami from foetuses or offspring at various ages. These modelsAvailable online 3 January 2011hormone (MSH), a key regwhich is therefore a prime tReceived in revised form 6 October 2010Accepted 29 October 2010

    hypothalamic neuropeptideReview

    Epigenetic changes in the hypothalamic pro-opiomelanocortin gene: A mechanismlinking 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, UKb Faculty of Medical and Human Sciences, University of Manchester, UK

    a b s t r a c ta r t i c l e i n f o

    Article history:Received 9 August 2010

    Maternal undernutrition is associated with programming of obesity in offspring. While previous evidence haslinked programming to the hypothalamic, pituitary, and adrenal (HPA) axis it could also affect the

    s which regulate food intake and energy balance. Alpha melanocyte stimulatingulator of these neuronal pathways, is derived from pro-opiomelanocortin (POMC)

    j ourna l homepage: www.e lsev ie r.com/ locate /e jphard Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill178, +44 161 275 5180 (Secretary).hite).

    11 Published by Elsevier B.V. All rights reserved.

  • POMC-derived peptides (Cone, 2005; Pritchard et al., 2003, 2002;Pritchard and White, 2007). Hypothalamic POMC neuronal excitabil-ity, hypothalamic POMCmRNA and circulatingMSH are decreased inrodent models of leptin or leptin-receptor deciency (Forbes et al.,2001; Korner et al., 1999; Korner et al., 2001; Mizuno et al., 1998;Thornton et al., 1997; Turner et al., 2006) and this can be reversed byleptin administration (Cowley et al., 2001; Forbes et al., 2001; Korneret al., 2001; Schwartz et al., 1997; Thornton et al., 1997).

    It is well known that in the pituitary, POMC transcription isinhibited by glucocorticoids. Hypothalamic expression of POMC canalso be regulated by glucocorticoids, but there are differing observa-tions on how this occurs and these are discussed further in Section 4.3.Some POMC neurons also possess receptors for insulin and co-administration of the melanocortin MC4 receptor antagonist,SHU9119, prevents the anorectic effects of insulin (Benoit et al.,2002). Reductions in POMC mRNA levels were observed in conjunc-tion with decreased plasma insulin concentrations in adrenalecto-mised versus sham-operated rats demonstrating the regulatory effectof glucocorticoids on this process (Savontaus et al., 2002) (Fig. 1).Moreover, decreases in hypothalamic POMC mRNA caused by fastingwere prevented by intracerebroventricular (i.c.v) injection of insulin(Benoit et al., 2002). POMC neurons are also regulated by glucose andthey express components of the glucose-sensing ATP-sensitivepotassium channels and respond to a reduction in extracellularglucose concentration by decreasing neuronal ring (Gyte et al., 2007;Ibrahim et al., 2003). This suggests a key role for POMC in the centralmelanocortin regulation of glucose homeostasis (Obici et al., 2001).

    2.3. The role of POMC in food intake and energy balance

    The importance of POMC in food intake and energy balance isexemplied by mutations in the POMC gene resulting in an obese

    195A. Stevens et al. / European Journal of Pharmacology 660 (2011) 1942011. Introduction

    Hypothalamic POMC is implicated in the development of bothobesity and diabetes, each of which has a major impact on humanhealth. Indeed, metabolic syndrome, which includes obesity, cardio-vascular disease and diabetes, affects up to 25% of the population inthe USA (Ford et al., 2002). Although there is increasing evidence forcandidate genes involved in the development of obesity there is still alack of clarity of how this occurs in the majority of cases. One area ofinterest is the effect of maternal nutrition on obesity in the offspring.This association was identied in survivors of the Dutch famine of19441945 where there was a correlation between maternalundernutrition and subsequent obesity in adult offspring (Ravelliet al., 1976). This led to the concept being termed maternalprogramming (Seckl, 2004).

    Programming of the foetusmight occur to prepare the offspring foran adverse postnatal environment (Kapoor, 2006). However thesechanges can be associated with offspring having lower birth weight,increased propensity to develop an obese phenotype in later life andincreased susceptibility to cardiovascular disease and diabetes(Martin-Gronert and Ozanne, 2005; Rhodes et al., 2009).

    There are many factors that might inuence the outcome ofdevelopmental programming. These include the timing of the insult,the number of foetuses and the sex of the offspring. Furthermore thetype of insult is also important, which along with stress (Seckl andHolmes, 2007) includes nutritional effects that could be mediated bythe hypothalamus (Bertram and Hanson, 2002).

    2. Programming of food intake and energy balance

    2.1. Neuropeptide regulation of food intake

    Energy homeostasis is tightly controlled in the hypothalamusdespite uctuations in energy consumption and expenditure.Therefore the foetal hypothalamic appetite regulatory network is aprime candidate for maternal programming. Hypothalamic regula-tion of food intake and energy balance in the arcuate nucleus (Fig. 1)depends on a complex array of neuropeptides but most is knownabout the anorexigenic pro-opiomelanocortin (POMC) and cocaineamphetamine regulated transcript expressing neurons and theorexigenic neuropeptide Y and agouti related peptide expressingneurons (Challis and Yeo, 2002). The activation of POMC neuronsresults in the cleavage of the prohormone, POMC, to MSH and therelease of MSH in the paraventricular nucleus (Pritchard et al.,2003, 2002; Pritchard and White, 2007).

    In situations of positive energy balance, leptin released fromadipocytes, stimulate