Astrocytes mediate GLP-1 effects on energy balance

项目概要： 本研究主要探讨星形胶质细胞在大鼠尾侧孤束核（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-1 R）激动剂的摄食抑制作用 （毒蜥外泌肽-4和利拉鲁肽，FDA批准用于治疗糖尿病和肥胖）是介导的，部分地， 通过CNS中的直接GLP-1 R信号传导。然而，特异性GLP-1 R表达细胞核和细胞内 CNS内介导GLP-1 R配体代谢作用的机制仍基本未知。 虽然集体文献清楚地支持神经元加工在介导GLP-1对神经元的作用中的作用，但是， 食物摄入，GLP-1 R信号对星形胶质细胞能量平衡控制的贡献尚未被证实。 考察考虑到星形胶质细胞对于通过细胞外基质调节细胞外空间中的谷氨酸是关键的， GLAST和GLT-1转运蛋白，考虑GLP-1 R配体直接作用于GLAST和GLT-1转运蛋白的想法是有趣的。 星形胶质细胞在能量平衡相关的核中接收神经元能输入。新界南总区是首个 核接收和处理餐内迷走神经介导的神经营养能饱足信号， 胃肠道因此，在我们令人兴奋的初步研究的基础上， 应用程序将直接检验NTS内星形胶质细胞中GLP-1 R信号传导在生理上是 并且与食物摄入的调节相关。使用最先进的尖端技术 我们将研究以下具体目标：[1]确定体内 能量平衡控制中NTS星形胶质细胞上GLP-1 R信号传导的生理相关性。[2]检查GLP-1 R 使用活细胞Ca++对NTS星形胶质细胞作为迷走神经-NTS介导的神经传递的调节剂的信号传导 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-1 R活化。这项研究将为新一轮的 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。

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.