! PROJECT SUMMARY/ABSTRACT The prevalence and severity of childhood obesity have increased dramatically and are coupled with alarming 30% rise in the prevalence of type 2 diabetes (T2D) in youth over the last decade. Mounting evidence suggests that exposures to maternal obesity and/or gestational diabetes mellitus (GDM) in utero contribute to these increases in childhood obesity and T2D. Studies from our group and others have shown that children who were exposed in utero to maternal obesity or GDM have greater adiposity and a higher risk for developing T2D compared to unexposed children. Studies in siblings discordant for maternal exposures suggest that the risk is in excess of that attributable to genetics and shared environment. The biological underpinnings of such maternal-fetal programming are poorly understood. Provocative studies in animal models reveal that intrauterine exposure to maternal obesity and/or diabetes results in alterations in the development of the hypothalamus, a brain area that is critical for the regulation of appetite and glucose homeostasis, leading to obesity and T2D later in life. To date, no studies have investigated the effects of exposure to maternal obesity or GDM on brain appetite pathways in humans. The overarching goal of this proposal is to test the hypothesis that in utero exposure to maternal obesity and/or GDM alters the structure and function of brain appetite pathways in ways that adversely impact energy balance and increases future risk for obesity and T2D in humans. Overall, these studies are highly innovative and have the potential to translate mechanistic findings in humans into early intervention strategies aimed at preventing the vicious cycle of maternal obesity/GDM and childhood obesity and T2D. !