Neuroendocrine Systems involved in Early-life Programming for Obesity and Diabetes

! 项目总结/摘要 儿童肥胖症的患病率和严重程度急剧增加， 在过去的十年中，青年2型糖尿病（T2 D）的患病率上升了30%。越来越多的证据 表明母体在子宫内暴露于肥胖和/或妊娠期糖尿病（GDM）有助于 儿童肥胖和T2 D的增加。我们小组和其他人的研究表明， 那些在子宫内暴露于母亲肥胖或GDM的人有更大的肥胖和更高的发展风险， T2 D与未接触的儿童相比。对母亲暴露不一致的兄弟姐妹的研究表明， 风险超过了遗传和共同环境造成的风险。这种生物学基础 对母胎编程的了解很少。在动物模型中进行的挑衅性研究表明， 子宫内暴露于母体肥胖和/或糖尿病导致胎儿发育的改变， 下丘脑，一个对调节食欲和葡萄糖稳态至关重要的大脑区域，导致 肥胖症和T2 D。到目前为止，还没有研究调查暴露于母亲肥胖的影响 或GDM对人类大脑食欲通路的影响。这项提案的首要目标是检验这一假设 在子宫内暴露于母体肥胖和/或GDM改变了大脑食欲的结构和功能， 这些途径对能量平衡产生不利影响，并增加肥胖和T2 D的未来风险， 人类总的来说，这些研究具有高度创新性，并有可能将机械发现转化为 人类的早期干预策略，旨在防止产妇肥胖/GDM的恶性循环， 儿童肥胖和T2 D。 !

! 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. !