Leptin and development of glucagon-like peptide-1(GLP-1)neural circuits controlling ingestive behavior

 描述(申请人提供)：儿童肥胖症在美国和国际上都在增加，这使年轻人一生都面临着毁灭性的和代价高昂的健康问题。调节代谢动态平衡的神经网络必须得到适当的发展，才能在成年后正常发挥作用。在异常环境条件下发育的神经回路可能会被破坏，不再正常工作，这可能会导致肥胖和相关的负面健康后果。后脑的孤束核(NTS)接受并整合内脏营养状态，主要将这些信息发送到下丘脑室旁核(PVH)，该核协调能量平衡和神经内分泌反应。研究表明，NTS神经元中的瘦素受体(LepRb)影响食物摄取和代谢率。除了瘦素在饱腹感信号中的作用外，它还在发育过程中作为一种神经营养因子发挥作用。瘦素是正常所必需的 轴突从下丘脑弓状核向下丘脑下丘脑室旁核生长。由于瘦素受体在发育过程中由NTS中的神经元表达(包括很大比例的GLP-1神经元)，瘦素可能指导这一途径的形成。在特定目标1中提出的实验将测试从NTS中的GLP-1神经元到PVH的神经投射的正常发展是否需要瘦素。基因定向轴突标记和免疫组织化学将被用于可视化和量化NTS中的GLP-1神经元及其在发育和成年期缺乏瘦素的Lepob/ob小鼠中的投射。在特定目的2中提出的实验将利用分子遗传学方法来确定瘦素对NTS GLP-1神经元的神经营养作用的作用部位，并表征这一途径的生理作用。总之，这些研究有望建立从NTS到PVH的GLP-1投射通路，作为决定代谢生理学重要方面的发育可编程底物。

 DESCRIPTION (provided by applicant): Childhood obesity has increased in the United States and internationally, which sets up young people for a lifetime of devastating and costly health problems. The neural networks that regulate metabolic homeostasis must develop appropriately in order to function properly in adulthood. Neural circuits that develop under abnormal environmental conditions can become disrupted and no longer function normally, which can lead to obesity and associated negative health consequences. The nucleus of the solitary tract (NTS) in the hindbrain receives and integrates visceral nutritional status, and primarily sends this information to the paraventricular nucleus of the hypothalmus (PVH), which coordinates energy balance and neuroendocrine responses. Leptin receptors (LepRb) in NTS neurons have been shown to impact food intake and metabolic rate. In addition to leptin's role in satiety signaling, it also functions as a neurotrophic factor in development. Leptin is required for normal axon outgrowth from the arcuate nucleus of the hypothalamus to the PVH. Because leptin receptors are expressed by neurons in the NTS during development (including a large proportion of GLP-1 neurons), leptin may direct formation of this pathway. Experiments proposed in Specific Aim 1 will test whether leptin is required for normal development of neural projections from GLP-1 neurons in the NTS to the PVH. Genetically targeted axonal labels and immunohistochemistry will be used to visualize and quantify GLP-1 neurons in the NTS and their projections in leptin-deficient Lepob/ob mice in development and adulthood. Experiments proposed in Specific Aim 2 will utilize a molecular genetic approach to establish the site of action for leptin's neurotrophic action on NTS GLP-1 neurons and characterize the physiological role of this pathway. Together these studies promise to establish the GLP-1 projection pathway from the NTS to the PVH as a developmentally programmable substrate that determines significant aspects of metabolic physiology.