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

描述（由申请人提供）：肥胖是西方社会最普遍的疾病之一。这种能量平衡失调的影响是广泛的，代价是高昂的。饮食和生活方式的改变对大多数肥胖和超重人群产生有意义的、持久的体重减轻是无效的，这表明寻找有效的药理学策略来产生体重减轻的迫切重要性。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，并且这些药物在人类和动物模型中具有减少食物摄入和体重的额外作用。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（尤其是可口食物）的机制，可能会为有效的肥胖治疗提供见解。本提案的主要目标是培训研究金申请人使用各种体内、体外和离体技术，以探索尾侧脑干GLP-1受体表达神经元在整合能量状态信号以及GLP-1受体激活导致的摄食量和体重长期减少中的作用。具体目的I检验了cAMP反应元件结合蛋白（CREB）（一种基因表达的细胞内介质）是GLP-1受体激活的持续能量平衡效应所必需的假设。腺相关病毒（AAV）介导的孤束内侧核（mNTS）（GLP-1信号传导和能量状态信号更广泛整合的关键尾侧脑干结构）中CREB的敲低将用于确定GLP-1受体信号传导对能量平衡和血糖控制相关的行为和生理终点的影响对mNTS CREB的需求。此外，将使用细胞培养模型 探索GLP-1受体激活所募集的细胞内信号通路，以确定CREB激活所必需的信号通路。特定目的II中拟定的实验检测了后脑GLP-1受体信号传导的慢性选择性改变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。本提案中的实验使用体内、体外和离体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.