Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius

项目摘要 肥胖症的惊人流行带来了重大的公共健康和经济后果。的 开发更有效的减肥疗法是至关重要的，需要基础科学研究， 描述进食行为的神经控制。黑皮质素信号，通过黑皮质素4受体 孤束核（NTS）中的MC 4受体（MC 4 Rs）通过减少食物摄入来控制能量平衡 以及通过放大餐内胃肠（GI）来源的饱食而增加能量消耗 信号.然而，MC 4 R信号转导在NTS中的作用机制尚不清楚， NTS黑皮质素信号和其他激素系统在NTS水平上的相互作用， 没有得到充分的探索。本研究旨在验证内源性预- 突触后NTS MC 4 R活性放大NTS神经信号传导、食物摄入和体重 抑制和能量消耗的增加引起的GI-衍生饱足信号 胆囊收缩素（CCK）和胰高血糖素样肽-1（GLP-1）。具体目标I将使用体内光纤光度法 研究CCK-和GLP-1-诱发的NTS神经活动的双向调节，通过后脑递送 MC 4 R激动剂MTII或拮抗剂Shu 9119。我们假设这两者引起的神经活动 饱足信号将被外源MTII放大并被Shu 9119减弱。我们假设 NTS神经活动的增强将导致饱足信号和能量消耗的放大，我们预计， NTS提供MTII也增加能量消耗以及食物摄入和体重抑制 外周给药CCK或GLP-1的作用。具体目标II将利用腺相关病毒（AAV）- 编码cre-重组酶，递送至迷走神经的结状神经节或MC 4 Rlox/lox的NTS 小鼠选择性地敲低在迷走神经突触前传入或突触后NTS神经元上表达的MC 4 R， 分别我们将分析每组小鼠的进食行为和能量消耗， 分离突触前和突触后NTS MC 4 R对食物摄入、能量消耗的内源性贡献 体重控制。我们将继续使用这种策略来研究突触前和突触后MC 4 R的作用。 在介导外源性NTS MTII递送的摄入抑制和能量消耗增强效应中 并增强CCK和GLP-1的厌食作用。最后，我们将开始表征表型 NTS内MTII激活的神经元。通过确定MC 4 R的功能相关性和机制， 这些研究将有助于识别一种新的NTS MC 4 R激活电路， 可以通过药理学方法来控制，以减少食物摄入量和体重。

Project Summary The astounding prevalence of obesity presents major public health and economic consequences. The development of more effective therapeutics for weight loss is paramount and requires basic science research to characterize the neural control of feeding behavior. Melanocortin signaling, through melanocortin 4 receptors (MC4Rs) in the nucleus tractus solitarius (NTS) contributes to energy balance control by reducing food intake and increasing energy expenditure via amplification of within-meal gastrointestinally (GI)-derived satiation signals. However, the mechanism of MC4R signaling within the NTS is not clear and the translational significance of the interaction between NTS melanocortin signaling and other hormonal systems at the level of the NTS has not been adequately explored. The proposed research aims to test the hypothesis that endogenous pre- and postsynaptic NTS MC4R activity amplifies NTS neural signaling, food intake and body weight suppression and energy expenditure increases evoked by the GI-derived satiation signals cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). Specific Aim I will use in vivo fiber photometry to examine bidirectional modulation of CCK- and GLP-1-evoked NTS neural activity by hindbrain delivery of the MC4R agonist MTII or antagonist Shu9119. We hypothesize that neural activity evoked by either of these satiation signals will be amplified by exogenous MTII and attenuated by Shu9119. As we hypothesize that potentiation of NTS neural activity will result in amplified satiation signaling and energy expenditure, we expect NTS delivered MTII to also enhance energy expenditure as well as the food intake and body weight suppressive effects of peripherally administered CCK or GLP-1. Specific Aim II will utilize an adeno-associated virus (AAV)- encoding cre-recombinase delivered to either the nodose ganglion of the vagus nerve or to the NTS of MC4Rlox/lox mice to selectively knockdown MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons, respectively. We will analyze feeding behavior and energy expenditure in each of these groups of mice to dissociate the endogenous contribution of pre- and postsynaptic NTS MC4Rs to food intake, energy expenditure and body weight control. We will go on to use this strategy to examine the role of pre- and postsynaptic MC4Rs in mediating the intake-suppressive and energy expenditure-enhancing effects of exogenous NTS MTII delivery and in potentiating the anorectic actions of CCK and GLP-1. Finally, we will begin to characterize the phenotype of MTII-activated neurons within the NTS. By determining the functional relevance and mechanism of MC4R signaling within the NTS, these studies will contribute to identification of a novel NTS MC4R-activated circuit that may be manipulated through pharmacological approaches to reduce food intake and body weight.