Neuroendocrinology of Energy Balance Control

描述(由申请人提供)：拟议的研究重点是神经肽类胰高血糖素-1(GLP-1)及其通过中枢神经系统(CNS)的作用来控制食物摄入量和体重的作用。FDA批准的GLP-1受体(GLP-1R)激动剂用于治疗II型糖尿病(T2 DM)可以改善血糖调节，此外，在人类和动物模型中都能显著减少食物摄入量和体重。因此，长效GLP-1R激动剂作为一种潜在的治疗肥胖症的药物最近受到了关注。GLP-1信号在迷走神经传入、后脑和下丘脑核团[如孤束核(NTS)和下丘脑室旁核]中的重要性被证实为动态平衡或基于需要的摄食量控制。然而，鉴于导致人类肥胖的过度食物摄入量不仅仅是由代谢需求驱动的，因此研究和更好地定义食物摄入量的非稳态控制的神经基础是至关重要的。由于GLP-1R也在与奖赏和认知过程相关的大脑区域表达，因此确定GLP-1信号对摄食的非稳态控制的机制是该应用的重点和重点。同样清楚的是，如果研究确定特定的中枢神经系统核团和机制(S)介导GLP-1的S对能量平衡的影响，以及调查其他也有助于能量平衡的神经化学系统是否与中枢神经系统GLP-1R介导的摄取抑制作用相互作用并增强其作用，那么肥胖的治疗将会取得更大的进展。本方案中的实验将利用神经药理学、行为学、分子生物学、遗传学、免疫组织化学、电生理学和先进的外科技术相结合的新方法来研究：[1]来自胃肠道的迷走神经饱足信号是否部分通过NTS GLP-1投射到中脑边缘奖赏系统的核[如腹侧被盖区(VTA)和伏隔核(NAC)]来抑制摄食；[2]多巴胺和谷氨酸能机制是否介导了VTA和NAC中GLP-1R信号的摄取抑制效应；[3]NTS GLP-1R介导的转录和蛋白质合成的变化与其他NTS调节的厌食系统的摄入量和体重抑制效应相结合并增强。拟议的整体研究将为开发更有效的GLP-1R介导的肥胖症治疗方法提供一个框架。此外，结果可能有助于确定潜在的目标 用于联合药物治疗，以提高以GLP-1为基础的药物的食物摄入量和体重抑制作用。

DESCRIPTION (provided by applicant): The proposed research focuses on the neuropeptide glucagon-like peptide-1 (GLP-1) and its role in controlling for food intake and body weight through action in the central nervous system (CNS). FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. The importance of GLP-1 signaling on vagal afferents and in hindbrain and hypothalamic nuclei [e.g. nucleus tractus solitarius (NTS) and paraventricular hypothalamus] is established for the homeostatic or need-based control of food intake. However, given that the excessive food intake that contributes to human obesity is not driven by metabolic need alone, it is critical to examine and better define the neural basis of non-homeostatic controls of food intake. As GLP-1R are also expressed in brain regions associated with reward and cognitive processes, determining the mechanism by which GLP-1 signaling contributes to the non-homeostatic control of feeding is a priority and focus of this application. It is also very clear that more progress could be made in the treatment of obesity if research identifies specific CNS nuclei and mechanism(s) mediating GLP-1's effects on energy balance, as well as investigate whether other neurochemical systems that also contribute to energy balance interact with and enhance CNS GLP-1R-mediated intake inhibitory effects. Experiments in this proposal will utilize novel approaches that combine neuropharmacological, behavioral, molecular, genetic, immunohistochemical, electrophysiological, and advanced surgical techniques to examine: [1] whether vagal satiation signals from the gastrointestinal tract inhibit food intake in part via mediation by NTS GLP-1 projections to the nuclei of the mesolimbic reward system [e.g. ventral tegmental area (VTA) and nucleus accumbens (NAc)]; [2] whether dopaminergic and glutamatergic mechanisms mediate the intake suppressive effects of GLP-1R signaling in the VTA and NAc; [3] NTS GLP-1R-mediated transcription and protein synthesis changes that integrate with and potentiate intake and body weight suppressive effects of other NTS-modulated anorectic systems. The overall research proposed will provide a framework for development of more effective GLP-1R-mediated treatments for obese individuals. In addition, results may help identify potential targets for combination drug therapy to enhance the food intake and body weight suppressive effects of GLP-1- based pharmaceuticals.