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

项目摘要/摘要 中枢神经系统(CNS)对新陈代谢的调控在维持能量动态平衡方面起着关键作用。 胰高血糖素样肽1(GLP-1，由GCG编码)，由位于 这个 孤束核抑制进食。中枢和外周GLP-1独立工作以 抑制喂食 。然而，在中枢神经系统中介导内源性GLP-1作用的细胞和电路机制 人们对此仍然知之甚少。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。 解决GLP-1的中枢神经系统机制将有助于开发更多针对肥胖干预的定制治疗方法。 我们的首要目标是从机制上了解内源性GLP-1的释放及其在脑内的作用。 CNS以单元类型和电路定义的方式。在之前的一项研究中， 我们发现NTS GLP-1投影到 下丘脑室旁核(PVN)增强谷氨酸能突触传递，即 足以抑制食物的摄取，而PVN GLP-1R的消融会导致暴食和肥胖。这些结果 强调中央GLP-1在调节能量稳态方面的潜在作用。然而，GLP-1信号是 与背运动形成突触的PVN区GLP-1R神经元的异质性所致的复杂性 迷走神经核团(DMV)神经元释放谷氨酸，同时也释放g-氨基丁酸。 终纹床核(BNST)。DMV和BNST可能以不同的方式调节摄食行为，即 动态平衡与享乐性喂养，但PVN GLP-1R神经元到DMV和BNST投射的作用 游戏仍未被探索。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导，我们发现了GLP-1释放到PVN的时间 与吃比赛成反比。因此，我们假设电路和神经元亚型依赖 下丘脑室旁核中的内源性GLP-1信号调节进食模式(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的时间动力学 在摄食期间，下丘脑室旁核的释放和神经元活动；我们将检验GLP-1的假设 信号通过不同的神经通路调节动态平衡和动力摄食。这样做的结果 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 针对进食障碍和肥胖的神经肽靶向临床干预措施的发展。

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.