Effects of altered glucose supply and adiposity on expression of hypothalamic energy balance regulatory genes in late gestation growth restricted ovine fetuses

Intra-uterine growth restriction (IUGR) predisposes obesity in adulthood. This may be due to altered fetal nutrition causing sustained changes within the developing hypothalamic energy balance regulatory system. Using our established ovine model of IUGR, 130-day singleton fetuses (term = 147 days) were obtained from growing adolescent mothers on control dietary intake (C), high intake (H) or H with growth hormone administration during either early (H + early GH) or late gestation (H + late GH) (n = 6/group). GH increased maternal glycemia for the duration of treatment. H and H + early GH fetuses showed IUGR compared with C fetuses; body weight was partially restored in H + late GH fetuses, with 40% increased adiposity. In the fetal hypothalamic arcuate nucleus (ARC), cocaine- and amphetamine-regulated transcript mRNA (anorexigenic) was decreased in H fetuses and correlated across all groups with total fetal liver glycogen. Neuropeptide Y, agouti-related peptide (orexigenic) and proopiomelanocortin (anorexigenic) mRNAs were not different between groups. Insulin receptor mRNA in the ARC was increased in H, H + early GH and H + late GH fetuses and correlated negatively with fetal plasma insulin. Leptin receptor mRNA in the ARC correlated positively with fetal plasma leptin concentration and fetal fat content. Therefore, in IUGR fetuses, a key anorexigenic neuropeptide is sensitive to altered glucose supply and the hypothalamic leptin-signaling pathway is altered prenatally by increased adiposity and leptinemia. These changes could impact on postnatal energy balance regulation.

► Late gestation ovine fetuses with variable glucose (nutritional) supply. ► Hypothalamic CART mRNA decreased in growth restricted fetuses. ► CART mRNA correlated with fetal liver glycogen content. ► NPY, AGRP and POMC mRNAs not different in growth restricted vs control fetuses. ► Hypothalamic leptin receptor mRNA correlated with fetal adiposity and leptinemia.