Galanin Control of Food Intake: Molecular, Neuroanatomical and Behavioral Bases

描述（由申请人提供）：甘丙肽是一种神经肽，被认为通过饮食脂肪依赖的正前馈机制促进食物摄入和脂肪沉积，这是随着西方饮食的兴起而肥胖蔓延的一个显著特性。然而，甘丙肽系统与暴饮暴食和脂肪积累的生理和治疗相关性仍然不确定，因为没有适当的工具来定义其内源性作用和介导受体亚型，行为机制和神经解剖部位的作用。目前的应用抓住了分子，药理学和行为学进展的融合，以确定甘丙氨酸系统如何在美味饮食存在时增加食物摄入和促进肥胖。Aim 1通过互补途径确定了介导甘丙肽摄氧和代谢作用的甘丙肽受体（GalR）亚型：在GalR缺陷小鼠中急性颅内输注甘丙肽和急性颅内输注最近可用的亚型偏好激动剂和拮抗剂。内源性甘丙肽信号在促进贪食和肥胖中的生理作用将在长期摄入高或低饱和脂肪饮食的GalR基因敲除突变小鼠中进行研究。目的2使用摄入/偏好曲线的浓度-反应分析、微观结构和递进比率分析，以及口服后反馈的实验操作来确定丙氨酸系统调节摄入的行为机制。Aim 3结合功能定位方法和局部短发夹RNA （shRNA）敲低GalR基因表达，以分子和神经解剖学特异性鉴定gal丙氨酸具有促氧作用的脑靶点。持续的、局部的GalR表达下调也将测试内源性下丘脑GalR系统对食物摄入、代谢和肥胖的生理影响，并具有脑区域和分子特异性。该项目的结果将有助于确定甘丙肽在美味高脂肪食物中促进肥胖的生理作用、分子、行为和神经解剖学的作用模式。针对这些活动的靶向治疗可能会被设计出来。全世界约有10亿人超重或肥胖，不分年龄、种族、民族和性别，这些情况增加了死亡率、发病率和经济成本。甘丙肽是一种神经肽，能促进啮齿动物的食物摄入和脂肪沉积，与肥胖风险有关。在这一建议中，我们开始确定丙氨酸促进食物摄入的行为、解剖和受体机制。甘丙氨酸受体信号在肥胖风险和适口饮食下暴饮暴食中的功能意义也将被确定。通过增加我们对能量稳态的分子控制的理解，结果可能会导致新的预防或治疗肥胖的选择，并将增加我们对食欲神经生物学的理解。

DESCRIPTION (provided by applicant): Galanin is a neuropeptide believed to promote food intake and fat deposition via a dietary fat-dependent positive feed-forward mechanism, a salient property given the spread of obesity with the rise of Western diets. However, the physiologic and therapeutic relevance of galanin systems for overeating and fat accrual has remained uncertain because the proper tools to define its endogenous role and mediating receptor subtype, behavioral mechanism and neuroanatomical sites of action were not available. The present application seizes upon a convergence of molecular, pharmacological and behavioral advances to determine how galanin systems increase food intake and promote adiposity when palatable diets are present. Aim 1 identifies the galanin receptor (GalR) subtype that mediates orexigenic and metabolic actions of galanin through complementary approaches: acute intracranial infusion of galanin in GalR deficient mice and acute intracranial infusion of recently available subtype-preferring agonists and antagonists. The physiologic role of endogenous galanin signaling in facilitating hyperphagia and obesity will be studied in mutant GalR knockout mice with long-term access to diets high or low in saturated fat. Aim 2 uses concentration-response analysis of intake/preference curves, microstructure and progressive ratio analyses, and experimental manipulation of post-oral feedback to identify the behavioral mechanism underlying galanin system modulation of intake. Aim 3 combines functional mapping approaches and local short hairpin RNA (shRNA) knockdown of GalR gene expression to identify, with molecular and neuroanatomical specificity, brain targets through which galanin has orexigenic action. Persistent, local knockdown of GalR expression also will test the physiologic influence of endogenous hypothalamic GalR systems on food intake, metabolism, and adiposity with both brain region- and molecular-specificity. Results from the project will help define the physiologic role and molecular, behavioral and neuroanatomical modes of action by which galanin promotes obesity in the presence of palatable, high-fat food. Targeted therapies against these activities could then potentially be devised. PUBLIC HEALTH RELEVANCE About 1 billion people worldwide are overweight or obese, cutting across age, race, ethnicity and gender, and these conditions increase mortality, morbidity, and economic costs. Galanin is a neuropeptide that promotes food intake and fat deposition in rodents and which is associated with obesity risk. In this proposal, we begin to identify the behavioral, anatomical, and receptor mechanisms of action by which galanin promotes food intake. The functional significance of galanin receptor signaling in obesity risk and overeating in the presence of palatable diets also will be determined. By increasing our understanding of this understudied molecular control of energy homeostasis, the results may lead to new preventative or therapeutic options for obesity and will increase our understanding of the neurobiology of appetite.