Central melanin-concentrating hormone neural pathways and obesity

项目总结/摘要 尽管为解决和扭转肥胖症流行做出了相当大的努力，但肥胖症仍然很高， 大脑在调节体重方面起着重要作用，无论是通过调节 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是至关重要的。黑色素浓集激素（MCH）是一种 一种神经肽，在大脑中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，MCH系统是 肥胖药物治疗的有前途的目标。目前，通过其作用的机制和神经部位， MCH调节能量平衡在很大程度上是未知的。本提案的总体目标是确定 MCH促进食欲过盛和饮食敏感性的神经作用部位和机制 诱发性肥胖Specific Aim 1A和1B利用两种新的病毒发生学RNA干扰方法来促进 室旁下丘脑（PVH）MCH系统功能丧失。然后动物们被挑战 用可口的高脂肪，高糖，西方自助餐饮食，以确定是否PVH MCH 系统在饮食诱导的肥胖的发展中起作用。实验在男性和女性中进行 大鼠，具有进一步研究性别差异的潜力，应 观察特定目的1C研究了MCH可能改变摄食效应的新分子机制， 即通过调节神经元初级纤毛的长度和/或纤毛信号传导的基因表达 蛋白腺苷酸环化酶3（AC 3）。特定目的2A研究了双角（ZI）MCH神经元的功能， 其行为功能尚未在进食行为方面单独研究的群体。基于 根据我们未发表的初步数据和最近发表的工作，我们提出ZI MCH神经元增加， 暴饮暴食行为我们将使用我们的MCH神经元特异性化学遗传学DREADD来研究这个问题。 approach.我们进一步计划确定ZI MCH神经元的下游解剖输出， 使我们能够在未来的研究中采用我们的双重病毒化学遗传学方法，以便更好地了解 这个独特的MCH神经元群体的多阶电路的功能。这些实验建立在 申请人K 01提案中的实验，专门设计用于产生必要的数据 申请人R 01申请。本文概述的研究还将为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，这是朝着 有效地开发基于该系统的肥胖药物疗法。

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.