Intrauterine growth restriction alters hypothalmic programming in the developing mouse brain

Intrauterine growth restriction (IUGR) creates altered programming in many organs, including the hypothalamus. Programming involves adaptive changes initiated to protect the survival of a fetus following IUGR, which can adversely influence the later response of genes that regulating energy balance. In male mice, IUGR coupled with rapid postnatal catch-up growth predisposes towards early onset obesity. One potential mechanism for this obesity is altered hypothalamic programming of intrahypothalamic cues involving prepro-orexin and prepro-MCH, two energy balance regulating genes as well as the extra-hypothalamic cues of peripheral hormones leptin and insulin. We therefore hypothesized that IUGR would alter hypothalamic programming of prepro-orexin and prepro-MCH genes in association with altered serum leptin and insulin levels in male mice at postnatal day 7 (P7) and P60. IUGR was induced via maternal thromboxane A2-analog infusion in the last week of C57BL/6J mouse gestation. Sham operated dams acted as controls. Sham and IUGR offspring were cross-fostered to unmanipulated dams and weaned to standard mouse chow at P21. In this mouse model, IUGR males, as compared to IUGR females, achieve rapid catch-up growth to sham males by P28 whereas IUGR females do not catch-up to sham females until P77. We measured mRNA levels via quantitative real-time RT-PCR, protein levels via Western immunoblotting, serum leptin and insulin levels via ELISA, and food intake from P21 to P60.