Glucagon-like peptide-1 in brainstem integration of energy balance control

描述(申请人提供)：肥胖是西方社会最常见的疾病之一。这种能源平衡失调的影响是广泛和代价高昂的。在大多数肥胖和超重人群中，改变饮食和生活方式对产生有意义的、持久的减肥无效，这表明找到有效的药物策略来实现减肥的迫切重要性。减肥疗法的一个潜在靶点是胰高血糖素样肽-1(GLP-1)系统。激活GLP-1受体的药物被FDA批准用于治疗与II型糖尿病相关的血糖控制障碍，这些药物还具有减少人类和动物模型的食物摄入量和体重的额外效果。更多地了解GLP-1受体激活产生持续体重减轻和抑制食物摄入的机制，特别是美味的食物，可能会为有效的服药提供洞察力。这项建议的主要目的是培训奖学金申请者在各种体内、体外和体外技术，以探索尾部脑干GLP-1受体表达神经元在能量状态信号整合中的作用，以及由于GLP-1受体激活而导致的食物摄入量和体重的长期减少。特定目的I验证了cAMP反应元件结合蛋白(CREB)是GLP-1受体激活所需的持续能量平衡效应所必需的假说。孤束内侧核(MNTS)是GLP-1信号转导和能量状态信号整合的关键脑干结构，腺相关病毒(AAV)介导的CREB基因敲除将被用来确定mNTS CREB对GLP-1受体信号在与能量平衡和血糖控制相关的行为和生理终点中的作用的需求。此外，还将使用细胞培养模型 探讨GLP-1受体激活所引起的细胞内信号转导途径，确定CREB激活所必需的信号转导途径。本实验旨在检测慢性选择性改变后脑GLP-1受体信号对能量平衡和血糖表型的影响，以及GLP-1受体信号转导的基因表达和变化。该提案中的实验使用体内、体外和体外技术的独特组合来调查所描述的研究问题。

DESCRIPTION (provided by applicant): Obesity is one of the most prevalent diseases in Western society. The implications of this disorder of energy balance are broad and costly. Dietary and lifestyle changes are ineffective to produce meaningful, long- lasting weight reduction in the majority of the obese and overweight population, suggesting the urgent importance of finding effective pharmacological strategies to produce weight loss. One potential target for weight loss therapies is the glucagon-like peptide-1 (GLP-1) system. Drugs that activate GLP-1 receptors are FDA-approved to treat the impairments in glycemic control associated with type II diabetes mellitus, and these drugs have the additional effects of reducing food intake and body weight in humans and animal models. Understanding more about the mechanisms by which GLP-1 receptor activation produces sustained body weight loss and inhibition of food intake, especially of palatable foods, may provide insight into effective obesit treatments. The main goal of this proposal is to train the fellowship applicant in a variety of in vivo, in vitro, and ex vivo techniques to probe the role of caudal brainstem GLP-1 receptor-expressing neurons in the integration of energy status signals and the long-term reductions in food intake and body weight produced by GLP-1 receptor activation. Specific Aim I tests the hypothesis that cAMP response element binding protein (CREB), an intracellular mediator of gene expression, is required for the sustained energy balance effects of GLP-1 receptor activation. Adeno-associated virally (AAV)-mediated knockdown of CREB in the medial nucleus of the solitary tract (mNTS), a key caudal brainstem structure for both GLP-1 signaling and the broader integration of energy status signals, will be used to determine the requirement of mNTS CREB for the effects of GLP-1 receptor signaling on behavioral and physiological endpoints related to energy balance and glycemic control. Additionally, a cell culture model will be utilized to probe the intracellular signaling pathways recruited by GLP-1 receptor activation to determine which are necessary for CREB activation. The experiments proposed in Specific Aim II test the effects of chronic selective alterations of hindbrain GLP-1 receptor signaling on energy balance and glycemic phenotypes, as well as gene expression and changes in GLP-1 receptor signal transduction. Experiments in this proposal use a unique combination of in vivo, in vitro, and ex vivo techniques to investigate the research questions described.