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

甘丙肽控制食物摄入：分子、神经解剖学和行为基础

• 批准号: 7849888
• 负责人: ERIC P ZORRILLA
• 金额: $ 3.39万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849888
• 关键词: Acute; Adipose tissue; Affinity; Age; Agonist; Amino Acids; Amygdaloid structure; Behavioral; Behavioral Mechanisms; Brain; Brain region; Carbohydrates; Chronic; Consumption; Coupled; Deposition; Desire for food; Diet; Dietary Fats; Eating; Energy Metabolism; Epidemic; Ethnic Origin; Fatty acid glycerol esters; Feedback; Food; GALR1 Galanin Receptor; Galanin; Gender; Gene Expression; Homeostasis; Hyperphagia; Hypothalamic structure; Infusion procedures; Intake; Knockout Mice; Lead; Maps; Mediating; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Neurobiology; Neuropeptides; Nucleus Accumbens; Obesity; Oral; Overweight; Physiological; Property; Psychological reinforcement; Public Health; Race; Rattus; Receptor Gene; Receptor Signaling; Recruitment Activity; Relative (related person); Resistance; Rewards; Rodent; Role; Signal Transduction; Site; Skeletal Muscle; Specificity; System; Testing; Therapeutic; base; dorsal raphe nucleus; economic cost; energy balance; feeding; galanin receptor; interest; lard; mortality; mutant; obesity risk; preference; public health relevance; receptor; receptor expression; response; saturated fat; small hairpin RNA; tool

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.

描述（由申请人提供）：甘丙肽是一种神经肽，据信可通过膳食脂肪依赖性正前馈机制促进食物摄入和脂肪沉积，考虑到随着西方饮食的兴起，肥胖症的蔓延，这是一个显着的特性。然而，甘丙肽系统与暴饮暴食和脂肪累积的生理和治疗相关性仍不确定，因为没有合适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学作用位点。本申请利用分子、药理学和行为学进步的融合来确定当存在可口饮食时甘丙肽系统如何增加食物摄入并促进肥胖。目标 1 通过补充方法鉴定甘丙肽受体 (GalR) 亚型，该亚型介导甘丙肽的食欲促进和代谢作用：在 GalR 缺陷小鼠中急性颅内输注甘丙肽，以及急性颅内输注最近可用的亚型偏好激动剂和拮抗剂。将在长期摄入高或低饱和脂肪饮食的突变型 GalR 基因敲除小鼠中研究内源性甘丙肽信号传导在促进食欲亢进和肥胖中的生理作用。目标 2 使用摄入/偏好曲线的浓度反应分析、微观结构和渐进比率分析以及口腔后反馈的实验操作来确定甘丙肽系统调节摄入的行为机制。目标 3 结合了功能图谱方法和 GalR 基因表达的局部短发夹 RNA (shRNA) 敲除，以分子和神经解剖学特异性来识别甘丙肽具有促食欲作用的大脑靶标。 GalR 表达的持续、局部敲低还将测试内源性下丘脑 GalR 系统对食物摄入、新陈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可口的高脂肪食物存在下促进肥胖的生理作用以及分子、行为和神经解剖学作用模式。然后可能会设计出针对这些活动的靶向疗法。 公共卫生相关性 全球约有 10 亿人超重或肥胖，无论年龄、种族、民族和性别如何，这些情况都会增加死亡率、发病率和经济成本。甘丙肽是一种神经肽，可促进啮齿动物的食物摄入和脂肪沉积，并与肥胖风险相关。在本提案中，我们开始确定甘丙肽促进食物摄入的行为、解剖和受体作用机制。甘丙肽受体信号传导在肥胖风险和在可口饮食的情况下暴饮暴食中的功能意义也将得到确定。通过增加我们对这种尚未研究的能量稳态分子控制的理解，这些结果可能会带来新的肥胖预防或治疗选择，并将增加我们对食欲神经生物学的理解。