Central melanin-concentrating hormone neural pathways and obesity

项目摘要/摘要 尽管在解决和扭转肥胖症流行方面做出了相当大的努力，肥胖症仍然居高不下 在美国很流行。大脑在调节体重方面起着重要作用，这既是通过调节 能量消耗和驱动进食行为，从而了解大脑如何调节能量 平衡对于开发有效的肥胖治疗方法至关重要。黑色素浓缩激素(MCH)是一种 一种神经肽，作用于大脑，通过增加食物摄入量和减少能量来促进体重增加 支出。由于其在能量平衡方程的两个方面的双重作用，妇幼保健系统是一个 肥胖症药物治疗的有前景的靶点。目前，其作用机制和神经部位 MCH调节能量平衡的机制在很大程度上是未知的。这项提案的首要目标是确定 MCH促进过度吞噬和饮食易感性的神经作用部位和机制 诱导性肥胖。特异性目标1A和1B利用两种新的病毒学RNA干扰方法来促进 下丘脑室旁核(PVH)中MCH系统功能的丧失。然后，动物们被挑战 用可口的高脂肪、高糖分、西式自助食谱来确定是否有PVH、MCH 系统在饮食诱导肥胖的发生发展中起着一定的作用。实验在男性和女性身上进行 有可能进一步研究性别差异的大鼠，应该是性二态效应 观察到的。特定目标1C研究了一种新的分子机制，通过该机制，MCH可以改变摄食效果， 即通过调节神经元初级纤毛的长度和/或纤毛信号的基因表达 蛋白腺酰环化酶3(AC3)。目的：研究Zi区MCH神经元的功能。 其行为功能尚未被单独研究的关于摄食行为的种群。基座 根据我们未发表的初步数据和最近发表的工作，我们认为Zi MCH神经元增加 暴饮暴食行为。我们将使用我们的MCH神经元特异性化学发生DREADD来研究这个问题 接近。我们进一步计划确定Zi MCH神经元的下游解剖输出，这将 使我们能够在未来的研究中使用我们的双重病毒化学遗传学方法，以便更好地理解 这一独特的MCH神经元群体的多阶回路的功能。这些实验建立在 这些实验来自申请者的K01提案，并专门设计来产生必要的数据 对于申请者R01申请。这里概述的研究还将对以下方面做出重大贡献 了解MCH信号在调节能量平衡中的作用，这是迈向 有效开展以该系统为基础的肥胖药物治疗。

Project Summary/Abstract Despite considerable efforts to address and reverse the obesity epidemic, obesity remains highly prevalent in the U.S. The brain plays an important role in regulating body weight, both through modulating energy expenditure and driving feeding behavior, and thus understanding how the brain regulates energy balance is critical for developing effective obesity treatments. Melanin-concentrating hormone (MCH) is a neuropeptide that acts in the brain to promote weight gain by increasing food intake and reducing energy expenditure. Due to its dual actions on both aspects of the energy balance equation, the MCH system is a promising target for obesity pharmacotherapies. Currently, the mechanisms and neural sites of action by which MCH modulates energy balance are largely unknown. The overarching goal of this proposal is to identify neural sites of action and mechanisms by which MCH promotes hyperphagia and susceptibility to diet induced obesity. Specific Aim 1A and 1B utilizes two novel virogenetic RNA interference approaches to promote a loss of function to the MCH system in the paraventricular hypothalamus (PVH). Animals are then challenged with a palatable high fat, high sugar, Western cafeteria diet in order to determine whether the PVH MCH system plays a role in the development of diet induced obesity. Experiments are performed in male and female rats, with the potential for further investigation into sex differences should sexually dimorphic effects be observed. Specific Aim 1C investigates a novel molecular mechanism by which MCH may alter feeding effects, namely by modulating the length of neuronal primary cilia and/or gene expression of the ciliary signaling protein adenylyl cyclase 3 (AC3). Specific Aim 2A investigates the function of zona incerta (ZI) MCH neurons, a population whose behavioral function has not been studied in isolation with regards to feeding behavior. Based on our unpublished preliminary data and recent published work, we propose that ZI MCH neurons increase binge-eating behavior. We will examine this question using our MCH neuron-specific chemogenetic DREADDs approach. We further plan to determine the downstream anatomical outputs of ZI MCH neurons, which will enable us to employ our dual virus chemogenetic approach in future studies in order to better understand the function of the multi-order circuitry of this unique population of MCH neurons. These experiments build on the experiments from the applicant's K01 proposal and are specifically designed to produce necessary data for the applicants R01 application. The studies outlined herein will additionally contribute significantly to understanding the role of the MCH signaling in regulating energy balance, which is an important step toward effectively developing obesity pharmacotherapies based on this system.