Effects of Maternal Diet on SNS Development in Offspring

描述（由申请人提供）：本项目的长期目标是更清楚地了解肥胖及其合并症、高血压和2型糖尿病的生物学基础。由于越来越多的证据将成人肥胖和相关疾病的患病率与胎儿和新生儿生命期间的身体生长指数联系起来，因此早期生活中的事件似乎会影响个体在以后几年获得这些疾病的可能性。这种应用建立在交感神经系统（SNS）是该过程中的关键中介的前提下，交感神经系统响应环境因素并改变受神经支配的组织的发育。对于SNS发展和肥胖可能特别重要的一个诱发因素是母体食物摄入的数量和质量。基于在发育诱导的肥胖的几种不同动物模型中交感神经支配的类似变化，本申请特别关注胰腺和腹膜后脂肪中SNS发育的营养诱导的改变。产妇暴露于富含精制碳水化合物（蔗糖和淀粉）的饮食增加SNS神经支配在这两个组织中，而摄入果糖或动物脂肪减少it. This建议的目的是更充分地描述产妇和新生儿的营养对交感神经和副交感神经的发展及其后果的影响，胰岛和腹膜后脂肪的结构和功能。研究将检查药物干预对发展中SNS的影响，在SNS增加的情况下采用化学交感神经切除术，在SNS减少的情况下使用神经保护剂，并评估其对组织质量和胰岛素分泌和作用的影响。最后，由于SNS参与怀孕的适应性反应，研究将检查雌性动物SNS发育改变对怀孕交感神经反应的后果及其对葡萄糖稳态的影响。从胎儿和新生儿到随后肥胖的途径可能遵循几条路径;一条涉及受损的早期生长，另一条涉及增强的早期生长。SNS发育的相应变化似乎伴随着实验动物生长的这些差异。确定生长，SNS发展和肥胖之间的联系提供了一个潜在的手段，以确定肥胖倾向的个人在生命的早期，以有效和适当的方式进行干预的最终目标。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand more clearly the biological basis for obesity and its co- morbid conditions, hypertension and Type 2 diabetes mellitus. Since increasing evidence links prevalence rates of obesity and related disorders in adults with indices of body growth during fetal and neonatal life, events in early life appear to influence the likelihood that an individual will acquire these conditions in later years. This application is founded on the premise that the sympathetic nervous system (SNS) is a key intermediary in this process, responding to environmental factors and altering development of the innervated tissues. One predisposing factor which may be especially important for SNS development and obesity is the quantity and quality of maternal food intake. Based upon similar changes in sympathetic innervation in several different animal models of developmentally-induced obesity, this application focuses specifically on nutrient-induced alterations in SNS development in pancreas and retroperitoneal fat. Maternal exposure to diets enriched in refined carbohydrates (sucrose and starch) increases SNS innervation in these two tissues, while intake of fructose or animal fat decreases it. The aims of this proposal are to characterize more fully the impact of maternal and neonatal nutrition on sympathetic and parasympathetic development and their consequences for structure and function of pancreatic islets and retroperitoneal fat. Studies will examine effects of pharmacological interventions on the developing SNS, employing chemical sympathectomy in circumstances of increased SNS and neuroprotective agents in settings of decreased SNS, and assessing their impact on tissue mass and on insulin secretion and action. Finally, since the SNS participates in adaptive responses to pregnancy, studies will examine the consequences of altered SNS development in female animals on sympathetic responses to pregnancy and their implications for glucose homeostasis. The route from fetal and neonatal life to subsequent obesity may follow several paths; one involves impaired and another enhanced early growth. Corresponding changes in SNS development appear to accompany these differences in growth in experimental animals. Identifying connections among growth, SNS development and obesity offers a potential means for identifying obesity-prone individuals early in life with the ultimate objective of intervening in an effective and appropriate manner.