Astrocytes mediate GLP-1 effects on energy balance

项目总结： 拟议的研究集中在星形胶质细胞在尾侧孤束核中的作用。 脑干介导高血糖素样多肽-1(GLP-1)的摄食和体重抑制作用。 越来越多的证据表明，GLP-1受体(GLP-1R)激动剂的摄食抑制作用 (Exendin-4和利拉鲁肽，FDA批准用于治疗糖尿病和肥胖症)在一定程度上是介导的， 通过中枢神经系统中直接的GLP-1R信号。然而，表达GLP-1R的特异性核和细胞 中枢神经系统内调节GLP-1R配体代谢效应的机制在很大程度上仍不清楚。 虽然集体文献清楚地支持神经元加工在介导GLP-1的S效应中的作用 食物摄入，星形胶质细胞上的GLP-1R信号对能量平衡控制的贡献尚未得到证实 检查过了。鉴于星形胶质细胞对细胞外间隙中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 星形胶质细胞在能量上平衡接受谷氨酸能输入的相关核团。新界南是首个中央 核团接受和处理迷走神经介导的餐内谷氨酸能饱足信号 胃肠道。因此，在我们令人兴奋的初步研究的基础上，在此提出的研究 应用将直接测试假设，即孤束核内星形胶质细胞中的GLP-1R信号是生理性的 并在药理上与食物摄入量的调节有关。使用最先进的尖端技术 和方法学途径，我们将检查以下具体目标：[1]在体内确定 孤束核星形胶质细胞GLP-1R信号在能量平衡调控中的生理学意义[2]检查GLP-1R 利用活细胞观察NTS星形胶质细胞作为迷走神经-NTS谷氨酸能神经传递调节剂的信号 成像和活体电生理学。[3]检查下列细胞内信号和细胞因子反应 GLP-1R激活NTS星形胶质细胞。提出的研究将为新一轮的 研究旨在阐明GLP-1-星形胶质细胞信号在调节能量平衡中所起的作用。

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.