Effects of prenatal exposures to maternal obesity and gestational diabetes on metabolic decline from childhood to adolescence and underlying neurobiological pathways

项目摘要/摘要 儿童肥胖率的上升与#年2型糖尿病患病率的惊人增长相结合 儿童和青少年。有证据表明，在子宫内暴露于母亲肥胖和/或妊娠 糖尿病(GDM)促成了这些上升趋势，而这些产前暴露对 代谢风险在青春期变得更加明显。虽然这样的生物机制 人们对母胎编程知之甚少，但在啮齿动物模型中令人信服的研究表明，在子宫内 暴露于母体肥胖和/或糖尿病会导致大脑通路异常发育，参与 能量平衡调节，导致肥胖和晚年的2型糖尿病。 我们小组是第一个研究子宫内暴露于母亲肥胖和妊娠期糖尿病对大脑通路的影响的小组。 使用一种开创性的方法结合神经成像方法和 儿童的代谢表型。到目前为止，我们的脑力研究队列中的横断面研究结果 为动物模型中看到的神经内分泌编程效应提供强有力的支持。最早的 我们已经确定的异常包括改变已知的参与能量平衡的大脑通路 监管。这些大脑的改变预示着儿童食物摄入量的增加和体重的增加。 在短期的随访中，并导致了本研究的主要假设： 在7-10岁儿童中观察到的神经标志物将预测过渡期间的代谢结果 到青春期，这是大脑发育和代谢下降的关键时期。儿童的产后行为包括 体力活动、饮食和睡眠也可能在调节或改变大脑通路连接的影响。 子宫暴露于孕妇妊娠期糖尿病和肥胖对儿童代谢轨迹的影响。我们将包括以下措施 这些行为，并探索这些途径，为未来关注生活方式的研究生成重要数据 行为。 这项对脑溢血队列进行长达六年的跟踪调查的纵向研究提供了独特的 有机会增进我们对大脑变化、肥胖、胰岛素抵抗和 肥胖症和糖尿病代际传递过程中早期的β细胞功能 风险。鉴于越来越多的孕妇患有肥胖症和妊娠期糖尿病， 未来几代人可能在很大程度上依赖于开发能够打破邪恶的干预措施 肥胖和糖尿病的跨代循环。拟议的研究将为 制定这类干预措施所需的知识库。

PROJECT SUMMARY/ABSTRACT Rising childhood obesity rates are coupled with an alarming increase in the prevalence of type 2 diabetes in children and adolescents. Evidence suggests that in utero exposures to maternal obesity and/or gestational diabetes mellitus (GDM) contribute to these upward trends, and the effects of these prenatal exposures on metabolic risk become more pronounced during adolescence. While the biological mechanisms of such maternal-fetal programming are poorly understood, compelling studies in rodent models show that in utero exposure to maternal obesity and/or diabetes causes abnormal development of brain pathways involved in energy balance regulation, leading to obesity and type 2 diabetes later in life. Our group was the first to study the effects in utero exposures to maternal obesity and GDM on brain pathways and metabolic outcomes in humans using a pioneering approach combining neuroimaging methods and metabolic phenotyping in children. To date, findings from cross-sectional studies in our BrainChild cohort provide strong support for the neuroendocrine programming effects seen in animal models. The earliest abnormality we have identified involves modification of brain pathways known to be involved in energy balance regulation. These brain modifications were predictive of increases in food intake and weight gain in children during short term follow-up and lead to the primary hypothesis of the present study: that differences in the neural markers observed in children at age 7-10 will be predictive of metabolic outcomes during the transition to adolescence, a critical time for brain development and metabolic decline. Child postnatal behaviors including physical activity, diet and sleep may also be mediating or modifying the effects of brain pathways linking in utero exposures to maternal GDM and obesity on child metabolic trajectories. We will include measures of these behaviors and explore these pathways to generate important data for future studies focusing on lifestyle behaviors. The proposed longitudinal study of the BrainChild cohort for up to six years of follow up provides the unique opportunity to advance our understanding of the interplay among brain changes, obesity, insulin resistance and beta cell function at early stages in the evolution of transgenerational transmission of obesity and diabetes risks. Given the growing number of pregnancies complicated by maternal obesity and GDM, the well-being of future generations may depend to an important degree on developing interventions that can break the vicious transgenerational cycle of obesity and diabetes. The proposed studies will contribute critical information to the knowledge base required for development of such interventions.