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

基本信息

批准号：
9661068
负责人：
MATTHEW R HAYES
金额：
$ 56.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/9661068
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 Income Interleukin-1 beta Interleukin-6 Interleukins Intestines Knowledge L Cells 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

项目摘要

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.

项目摘要：拟议的研究重点是星形胶质细胞在尾部的核心核（NTS）中的作用脑干介导食物摄入量和体重抑制胰高血糖素样肽-1（GLP-1）的抑制作用。积累的证据表明GLP-1受体（GLP-1R）激动剂的食物摄入抑制作用（Exendin-4和Liraglutide，FDA批准用于治疗糖尿病和肥胖的），部分介导通过中枢神经系统中的直接GLP-1R信号传导。但是，特定表达GLP-1R的核和细胞中枢神经系统中介导GLP-1R配体代谢作用的机制仍然很大未知。虽然集体文献显然支持神经元处理中介导GLP-1对的作用食物摄入，GLP-1R信号对星形胶质细胞对能量平衡控制的贡献尚未检查。鉴于星形胶质细胞对于通过 Glast和GLT-1转运蛋白，考虑到GLP-1R配体直接作用于上的想法很有趣能量平衡相关的核中的星形胶质细胞接收谷氨酸能输入。 NTS是第一个中央核接收和处理由膜内模糊介导的谷氨酸能饱满信号引起的胃肠道。因此，在我们令人兴奋的初步研究的基础上，研究中提出了研究应用将直接检验以下假设：NTS内星形胶质细胞中的GLP-1R信号传导在生理上是与药理学相关的食物摄入量。使用最先进的尖端技术和方法论方法我们将研究以下特定目的：[1]确定体内 GLP-1R信号在能量平衡控制中NTS星形胶质细胞上的生理相关性。 [2]检查GLP-1R 使用活细胞Ca ++的NTS星形胶质细胞上的信号传导作为迷走到NTS的调节剂成像和体内电生理学。 [3]检查以下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。提出的研究将为新浪潮提供新的框架研究旨在阐明GLP-1-胃细胞信号在调节能量平衡中发挥作用的作用。