Endocrine Abstracts (2012) 28 P165

Epigenetic changes in hypothalamic energy regulating pathways implicated in programming of adult offspring

Ghazala Begum1, Adam Stevens1, Anne Jaquiery3, John Challis2, Frank Bloomfield3 & Anne White1

1Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; 2Department of Physiology, University of Toronto, Toronto, ON, Canada; 3Liggins Institute, University of Auckland, Auckland, New Zealand.

There is increased prevalence of obesity and diabetes in offspring from mothers subjected to adverse conditions during pregnancy. Our previous work demonstrated that maternal undernutrition causes epigenetic changes in hypothalamic energy regulating networks in foetal sheep. We hypothesise that these changes will persist into adulthood. Therefore, this study examined the impact of maternal undernutrition on epigenetic and mRNA expression of hypothalamic regulators of energy balance. Maternal sheep were moderately undernourished for 60 days premating to 30 days post mating or fed ad libitum (control). After birth offspring were kept for 3–5 years. Offspring from undernourished mothers had altered body composition by DXA with increased %fat mass. Methylation of hypothalamic glucocorticoid receptor (GR) promoter was decreased in maternally underfed adult offspring (males: P<0.05, females: P<0.01), with increased GR mRNA expression (males: P<0.01, females: P<0.005). These changes are similar to those observed in maternally underfed foetal groups. Methylation changes were gene specific with no alterations in hypothalamic OCT4 promoter methylation. Analysis of hypothalamic neuropeptide mRNA expression revealed decreased pro-opiomelanocortin (POMC; female: P<0.005, male: P<0.01), increased agouti-related peptide (AgRP; males: P<0.005, females: P<0.005) and neuropeptide Y (NPY; P<0.005) expression in maternally underfed adult offspring. In summary, GR alterations in offspring from undernourished mothers were present in foetal life and continued into adulthood. The changes in methylation and associated hypothalamic neuropeptide mRNA expression are consistent with the obesity phenotype seen in the adult offspring. As a result, this study has implications for undernutrition and even dieting in pregnancy, suggesting that it could lead to obesity in the next generation.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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