Effects of Maternal Diet on SNS Development in Offspring

描述(申请人提供)：这个项目的长期目标是更清楚地了解肥胖的生物学基础及其共病条件，高血压和2型糖尿病。由于越来越多的证据将成年人肥胖和相关疾病的患病率与胎儿和新生儿期间的身体发育指数联系在一起，早期生活中的事件似乎会影响一个人在晚年感染这些疾病的可能性。这一应用建立在交感神经系统(SNS)是这一过程中的关键中介的前提下，SNS对环境因素做出反应并改变神经组织的发育。对SNS的发展和肥胖可能特别重要的一个诱因是母亲食物摄入量的数量和质量。基于在几种不同的发育性肥胖动物模型中交感神经的相似变化，该应用特别关注营养诱导的胰腺和腹膜后脂肪中SNS发育的变化。母亲摄入富含精制碳水化合物(蔗糖和淀粉)的饮食会增加这两个组织中的SNS神经支配，而摄入果糖或动物脂肪则会减少这种神经支配。这项建议的目的是更全面地描述母亲和新生儿营养对交感神经和副交感神经发育的影响及其对胰岛和腹膜后脂肪结构和功能的影响。研究将考察药物干预对发展中的SNS的影响，在SNS增加的情况下使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，并评估它们对组织质量和胰岛素分泌和作用的影响。最后，由于SNS参与了对怀孕的适应性反应，研究将检查雌性动物SNS发育变化对怀孕交感反应的影响及其对葡萄糖稳态的影响。从胎儿和新生儿的生活到随后的肥胖可能遵循几条途径；一条是受损，另一条是促进早期生长。SNS发育的相应变化似乎伴随着实验动物生长的这些差异。确定成长、社交网络发展和肥胖之间的联系提供了一种潜在的手段，可以在生命早期识别肥胖倾向者，最终目标是以有效和适当的方式进行干预。

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.