Synaptic and circuit mechanisms of central GLP-1 signaling in energy balance

项目总结/摘要 中枢神经系统（CNS）对代谢的控制在维持能量稳态中起着关键作用。 胰高血糖素样肽1（GLP-1，由Gcg编码），由位于脑内的不同神经元群分泌， 的 孤束核抑制进食中枢和外周GLP-1独立工作， 抑制摄食 .然而，在CNS中介导内源性GLP-1作用的细胞和回路机制 仍然知之甚少。这主要是由于存在不同的神经元亚型，复杂的中枢神经系统， 神经元连接，以及缺乏可以直接检测大脑中GLP-1释放的分子工具。 研究GLP-1的中枢神经系统机制将有助于开发更适合干预肥胖的治疗方法。 我们的首要目标是获得对内源性GLP-1释放及其功能的机制性理解， 以细胞类型和电路定义的方式来控制CNS。在之前的一项研究中， 我们发现NTS GLP-1投射到 下丘脑室旁核（PVN）增强突触传递， 足以抑制食物摄入，并且PVN GLP-1 R的消融导致暴饮暴食和肥胖。这些结果 强调了中枢GLP-1在调节能量稳态中的潜在作用。然而，GLP-1信号传导是 由于与背侧运动神经形成突触的PVN区域GLP-1 R神经元的异质性， 迷走神经（DMV）神经元的核，并释放谷氨酸，同时也释放g-氨基丁酸， 终纹床核（BNST）。DMV和BNST可能介导不同的食物摄入行为，即。 稳态与享乐喂养，但PVN GLP-1 R神经元到DMV和BNST投射的作用， 游戏尚未开发。此外，使用我们最近开发的用于GLP-1的光学传感器，称为Reporter 对于G蛋白偶联受体介导的传递，我们发现GLP-1释放到PVN的时间 与进食次数成反比因此，我们假设，电路和神经元亚型依赖 PVN中的内源性GLP-1信号传导调节进食模式（例如进餐时间和大小）、能量 支出和食物奖励。为了验证这一假设，我们将确定GLP-1的时间动态 我们将测试GLP-1在进食过程中的释放和PVN中的神经元活动的假设， 信号通过不同的神经元通路调节稳态和动机性进食。的结果 这项研究将促进我们对内源性GLP-1调节作用的概念性理解，促进 开发针对进食障碍和肥胖症的神经肽靶向临床干预措施。

Project Summary/Abstract Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis. Glucagon-like peptide 1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within the Nucleus Tractus Solitarius, suppresses feeding. Central and peripheral GLP-1 work independently to suppress feeding . However, the cellular and circuit mechanisms mediating endogenous GLP-1 action in the CNS are still poorly understood. This is mainly due to the presence of diverse neuronal subtypes, complex central neuronal connectivity, and the lack of molecular tools that can directly detect GLP-1 release in the brain. Addressing the CNS mechanism of GLP-1 will help develop more tailored treatment for intervention of obesity. Our overarching goal is to gain a mechanistic understanding of endogenous GLP-1 release and its functions in the CNS in a cell type- and circuit-defined manner. In a previous study, we found that NTS GLP-1 projection to the paraventricular hypothalamic nucleus (PVN) enhances glutamatergic synaptic transmission, which is sufficient to suppress food intake, and ablation of PVN GLP-1R causes overeating and obesity. These results highlight the potential role of central GLP-1 in regulating energy homeostasis. However, GLP-1 signaling is complex due to the heterogeneity of PVN region GLP-1R neurons which form synapses with the dorsal motor nucleus of the vagus nerve (DMV) neurons and release glutamate, while also releasing g-aminobutyric-acid in the bed nucleus of stria terminalis (BNST). DMV and BNST may mediate food intake behavior differentially, i.e. homeostatic vs. hedonic feedings, but the roles that the PVN GLP-1R neurons-to-DMV and BNST projections play remains unexplored. Moreover, using our recently developed optical sensors for GLP-1, termed Reporter for Transmission mediated by G protein-coupled Receptor, we found the timing of GLP-1 release into the PVN is inversely related to eating bouts. We thus hypothesize that circuit and neuronal subtype-dependent endogenous GLP-1 signaling in the PVN regulates eating patterns (e.g. meal timing and sizes), energy expenditure, and food rewards. To test this hypothesis, we will determine the temporal dynamics of GLP-1 release and neuronal activity in the PVN during feeding episodes; and we will test the hypothesis that GLP-1 signaling regulates homeostatic and motivational feeding via different neuronal pathways. The results of this study will advance our conceptual understanding of the regulatory effects of endogenous GLP-1, facilitating the development of neuropeptide-targeting clinical interventions for eating disorders and obesity.