Astrocytes mediate GLP-1 effects on energy balance

星形胶质细胞介导 GLP-1 对能量平衡的影响

• 批准号: 10207615
• 负责人: MATTHEW R HAYES
• 金额: $ 54.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207615
• 关键词: Affect; Agonist; Animal Model; Animals; Astrocytes; Attenuated; Basic Science; Body Weight; Brain; Brain Stem; Cell Nucleus; Cells; Chronic; Communication; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytokine Signaling; Data; Diabetes Mellitus; Disease; Dorsal; Dose; Eating; Electrophysiology (science); Endocrine; Extracellular Space; FDA approved; Female; Food Intake Regulation; GLAST Protein; GLP-I receptor; Gastric Balloon; Gastrointestinal tract structure; Glutamates; Hormones; Human; Hyperphagia; Image; Interleukin-1 beta; Interleukin-6; Interleukins; Knowledge; L Cell (Intestine); Ligands; Literature; MAP Kinase Gene; Mediating; Metabolic; Methodology; Nature; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pattern; Peripheral; Pharmacologic Substance; Pharmacology; Phosphorylation; Physiological; Play; Population; Process; Public Health; Rattus; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Satiation; Signal Transduction; Structure of area postrema; Synapses; Technology; Testing; Therapeutic; Time; Tissues; Viral; Weight Gain; base; blood glucose regulation; cell type; cytokine; designer receptors exclusively activated by designer drugs; dorsal motor nucleus; energy balance; exenatide; experimental study; gastrointestinal; glucagon-like peptide 1; glutamatergic signaling; gray matter; hindbrain; human model; improved; in vivo; incretin hormone; inhibitor/antagonist; knock-down; liraglutide; mRNA Expression; male; neurotransmission; novel; obesity treatment; preproglucagons; protein expression; relating to nervous system; response; sensor; uptake

Project Summary: The proposed research focuses on the role of astrocytes in the Nucleus Tractus Solitarius (NTS) of the caudal brainstem in mediating the food intake and body weight suppressive effects of glucagon-like peptide-1 (GLP-1). Accumulating evidence indicates that the food intake suppressive effects of GLP-1 receptor (GLP-1R) agonists (exendin-4 and liraglutide, FDA-approved for the treatment of diabetes and obesity) are mediated, in part, through direct GLP-1R signaling in the CNS. However, the specific GLP-1R-expressing nuclei and cellular mechanisms within the CNS that mediate the metabolic effects of GLP-1R ligands remain largely unknown. While the collective literature clearly supports a role for neuronal processing in mediating GLP-1's effects on food intake, the contribution of GLP-1R signaling on astrocytes to energy balance control has not been examined. Given that astrocytes are critical for the modulation of glutamate in the extracellular space via the GLAST and GLT-1 transporters, it is intriguing to consider the idea that GLP-1R ligands act directly on astrocytes in energy balance relevant nuclei that receive glutamatergic inputs. The NTS is the first central nucleus to receive and process within-meal vagally-mediated glutamatergic satiation signals arising from the gastrointestinal tract. Therefore, building on our exciting preliminary studies, research proposed in this application will directly test the hypothesis that GLP-1R signaling in astrocytes within the NTS is physiologically and pharmacologically relevant for the regulation of food intake. Using state-of-the-art, cutting-edge technology and methodological approaches we will examine the following Specific Aims: [1] Determine in vivo the physiological relevance of GLP-1R signaling on NTS astrocytes in energy balance control. [2] Examine GLP-1R signaling on NTS astrocytes as a modulator of vagal-to-NTS glutamatergic neurotransmission using live cell Ca++ imaging and in vivo electrophysiology. [3] Examine the intracellular signaling and cytokine responses following GLP-1R activation of NTS astrocytes. The research proposed will provide a novel framework for a new wave of research aimed at elucidating the role that GLP-1-astrocyte signaling plays in regulating energy balance.

项目概要： 拟议的研究重点是星形胶质细胞在尾部孤束核（NTS）中的作用 脑干介导胰高血糖素样肽-1 (GLP-1) 的食物摄入和体重抑制作用。 越来越多的证据表明 GLP-1 受体 (GLP-1R) 激动剂具有食物摄入抑制作用 （exendin-4 和利拉鲁肽，FDA 批准用于治疗糖尿病和肥胖症）部分介导， 通过 CNS 中的直接 GLP-1R 信号传导。然而，特定的表达 GLP-1R 的细胞核和细胞 CNS 内介导 GLP-1R 配体代谢作用的机制仍然很大程度上未知。 虽然集体文献明确支持神经元处理在介导 GLP-1 对 食物摄入量时，星形胶质细胞上的 GLP-1R 信号对能量平衡控制的贡献尚未被研究。 检查了。鉴于星形胶质细胞对于通过细胞外空间谷氨酸的调节至关重要 GLAST 和 GLT-1 转运蛋白，考虑 GLP-1R 配体直接作用于 接收谷氨酸输入的能量平衡相关核中的星形胶质细胞。 NTS 是第一个中央 细胞核接收和处理餐内迷走神经介导的谷氨酸饱足信号 胃肠道。因此，在我们令人兴奋的初步研究的基础上，本研究中提出的研究 应用程序将直接测试 NTS 内星形胶质细胞中 GLP-1R 信号传导在生理学上的假设 并在药理学上与食物摄入的调节相关。使用最先进的尖端技术 和方法论方法，我们将研究以下具体目标：[1] 确定体内 GLP-1R 信号对 NTS 星形胶质细胞在能量平衡控制中的生理相关性。 [2] 检查 GLP-1R 使用活细胞 Ca++ 作为迷走神经至 NTS 谷氨酸神经传递调节剂的 NTS 星形胶质细胞信号传导 成像和体内电生理学。 [3] 检查细胞内信号传导和细胞因子反应 NTS 星形胶质细胞的 GLP-1R 激活。拟议的研究将为新一波的研究提供一个新颖的框架 研究旨在阐明 GLP-1-星形胶质细胞信号传导在调节能量平衡中的作用。