Expression of energy balance regulatory genes in the developing ovine fetal hypothalamus at midgestation and the influence of hyperglycemia

Evidence suggests that the prenatal nutritional environment influences the risk of developing obesity, a major health problem worldwide. It is hypothesized that fetal nutrition influences the developing neuroendocrine hypothalamus, the integrative control center for postnatal energy balance regulation. The present aim was to determine whether relevant hypothalamic genes are expressed in midgestation and whether they are nutritionally (glucose) sensitive at this time. Hypothalami from a cohort of 81-day singleton sheep fetuses, with varying glycemia by virtue of maternal dietary and/or growth hormone treatment, were subject to in situ hybridization analysis for primary orexigenic, anorexigenic, and related receptor genes (term = 147 days, n = 24). Neuropeptide Y, agoutirelated peptide, proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), and insulin receptor mRNAs were all localized in the hypothalamic arcuate nucleus (ARC) of all fetuses, whereas leptin receptor mRNA was expressed more abundantly in the ventromedial hypothalamic nucleus. ARC expression levels of POMC and CART genes, but none of the other genes, were positively correlated with fetal plasma glucose concentrations. Therefore, key central components of adult energy balance regulation were already present as early as midgestation (equivalent to 22 wk in humans), and two anorexigenic components were upregulated by elevated glycemia. Such changes provide a potential mechanism for the prenatal origins of postnatal energy balance dysregulation and obesity.