Effects of Maternal Diet on SNS Development in Offspring

描述（由申请人提供）：该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表明，成人肥胖和相关疾病的患病率与胎儿和新生儿时期的身体生长指数有关，因此，生命早期发生的事件似乎会影响个人在今后几年患上这些疾病的可能性。这一应用的前提是交感神经系统（SNS）在这一过程中是一个关键的中介，响应环境因素并改变神经支配组织的发育。一个可能对SNS发育和肥胖特别重要的易感因素是母亲食物摄入的数量和质量。基于几种不同的发育性肥胖动物模型中交感神经支配的相似变化，本应用程序特别关注胰腺和腹膜后脂肪中营养诱导的SNS发育改变。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的SNS神经支配，而摄入果糖或动物脂肪则会减少这一神经支配。本建议的目的是更全面地描述产妇和新生儿营养对交感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。研究将检查药物干预对发育中的社交网络的影响，在社交网络增加的情况下使用化学交感神经切除术，在社交网络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，由于社交网络参与了对怀孕的适应性反应，研究将探讨雌性动物社交网络发育改变对怀孕交感神经反应的影响及其对葡萄糖稳态的影响。从胎儿和新生儿生命到随后的肥胖可能有几种途径；一种涉及早期发育受损，另一种涉及早期发育增强。在实验动物中，这些生长差异似乎伴随着SNS发育的相应变化。确定生长、社交网络发育和肥胖之间的联系，为在生命早期识别肥胖易感个体提供了一种潜在的手段，最终目的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.