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

能量平衡中枢 GLP-1 信号传导的突触和电路机制

• 批准号: 10530796
• 负责人: ZHIPING P. PANG
• 金额: $ 47.24万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530796
• 关键词: Ablation; Address; Affect; Agonist; Animals; Behavior; Body Weight decreased; Brain; Cell Nucleus; Clinical; Complex; Data; Development; Diabetes Mellitus; Eating; Eating Behavior; Eating Disorders; Electrophysiology (science); Energy Metabolism; Experimental Designs; FDA approved; Feeding Patterns; Feeding behaviors; Fiber; Food; Food Access; G-Protein-Coupled Receptors; Glutamates; Goals; Heterogeneity; Homeostasis; Human; Hyperphagia; In Situ Hybridization; Intervention; Lateral Hypothalamic Area; Link; Mediating; Metabolic Diseases; Metabolism; Molecular; Monitor; Motivation; Mus; Nervous System control; Neuraxis; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Physiological; Play; Population; Reporter; Rewards; Role; Signal Transduction; Structure of terminal stria nuclei of preoptic region; Subgroup; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Vagus nerve structure; Work; analog; brain dysfunction; cell type; dorsal motor nucleus; energy balance; feeding; gamma-Aminobutyric Acid; glucagon-like peptide 1; hedonic; individualized medicine; insight; interdisciplinary approach; neural circuit; neurochemistry; neuronal excitability; novel; obesity treatment; optical sensor; paraventricular nucleus; reduced food intake; tool; transmission process

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.

项目摘要/摘要 中枢神经系统（CNS）对代谢的控制在维持能量稳态方面起着关键作用。 胰高血糖素样肽1（GLP-1，由GCG编码），由位于不同的神经元分泌 这 肌核菌solitarius抑制喂养。中央和外围GLP-1独立工作 抑制进食 。但是，介导CNS中内源性GLP-1作用的细胞和电路机制 仍然很了解。这主要是由于存在多种神经元亚型，复杂的中央 神经元连通性以及缺乏可以直接检测到大脑中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量身定制的治疗方法以干预肥胖症。 我们的总体目标是对内源性GLP-1释放及其功能的机械理解 中枢神经系统以细胞类型和电路定义的方式。在先前的研究中， 我们发现NTS GLP-1投影 旁丘脑下丘脑核（PVN）增强了谷氨酸能突触传播，这是 足以抑制食物摄入量，而PVN GLP-1R的消融会导致暴饮暴食和肥胖。这些结果 强调了中央GLP-1在调节能量稳态中的潜在作用。但是，GLP-1信号是 由于PVN区域GLP-1R神经元的异质性，复合物与背运动形成突触 迷走神经（DMV）神经元和释放谷氨酸的核，同时还释放出G-氨基丁基酸性 Stria末端（BNST）的床核。 DMV和BNST可能会差异地介导食品摄入行为，即 体内稳态与享乐主义喂养，但PVN GLP-1R神经元至DMV和BNST预测的角色 游戏仍然没有探索。此外，使用我们最近开发的光学传感器用于GLP-1，称为记者 对于通过G蛋白偶联受体介导的透射率，我们发现GLP-1释放的时间释放到PVN中 与进食成反比。因此，我们假设该电路和神经元亚型依赖性 PVN中的内源性GLP-1信号传导调节饮食模式（例如，膳食时间和尺寸），能量 支出和食物奖励。为了检验这一假设，我们将确定GLP-1的时间动力学 喂养发作过程中PVN中的释放和神经元活性；我们将测试GLP-1的假设 信号传导通过不同的神经元途径调节体内平衡和动机喂养。结果的结果 研究将提高我们对内源性GLP-1的调节作用的概念理解，从而促进 开发针对饮食失调和肥胖症的神经肽临床干预措施。