Neuroendocrinology of Energy Balance Control

描述（由申请方提供）：拟定研究的重点是神经肽胰高血糖素样肽-1（GLP-1）及其通过在中枢神经系统（CNS）中的作用控制摄食量和体重的作用。FDA批准用于治疗II型糖尿病（T2 DM）的GLP-1受体（GLP-1 R）激动剂可改善血糖调节，此外，还可在人类和动物模型中显著降低摄食量和体重。因此，最近关注长效GLP-1 R激动剂作为肥胖症的潜在治疗。确定了GLP-1信号传导对迷走神经传入以及后脑和下丘脑核[例如孤束核（NTS）和室旁下丘脑]的重要性，以用于稳态或基于需求的摄食控制。然而，鉴于导致人类肥胖的过量食物摄入不仅仅是由代谢需要驱动的，因此检查并更好地定义食物摄入的非稳态控制的神经基础至关重要。由于GLP-1 R也在与奖赏和认知过程相关的脑区中表达，因此确定GLP-1信号传导促进摄食非稳态控制的机制是本申请的优先事项和重点。同样非常清楚的是，如果研究确定了介导GLP-1对能量平衡影响的特定CNS核和机制，以及研究其他也有助于能量平衡的神经化学系统是否与CNS GLP-1 R介导的摄入抑制作用相互作用并增强其作用，肥胖治疗可能会取得更大进展。本提案中的实验将利用结合联合收割机神经药理学、行为学、分子学、遗传学、免疫组织化学、电生理学和先进外科技术的新方法来检查：[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团[例如腹侧被盖区（VTA）和延髓核（NAc）];[2]多巴胺能和多巴胺能机制是否介导GLP-1 R信号在腹侧被盖区和NAc中的摄入抑制作用; [3] NTS GLP-1 R介导的转录和蛋白质合成变化与其他NTS调节的厌食系统的摄入和体重抑制作用整合并增强。拟议的整体研究将为开发更有效的GLP-1 R介导的肥胖个体治疗提供框架。此外，结果可能有助于确定潜在目标 用于联合药物治疗以增强基于GLP-1的药物的食物摄入和体重抑制作用。

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.