Peptidergic Control of Appetitive Ingestive Behaviors

食欲摄取行为的肽能控制

• 批准号: 8444178
• 负责人: Timothy Jon Bartness
• 金额: $ 32.14万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444178
• 关键词: ART protein; Acylation; Agonist; Animal Model; Animals; Automobile Driving; Behavior; Behavior Therapy; Belief; Body Weight decreased; Brain; Butyric Acids; Calories; Coenzyme A; Consumption; Diet; Disease; Eating; Endocrine; Fasting; Feeding behaviors; Figs - dietary; Fluorescent in Situ Hybridization; Food; Food deprivation (experimental); Genetic Engineering; Grant; Hamsters; Hereditary Disease; Home environment; Hormonal; Housing; Human; Hunger; Hyperphagia; Injection of therapeutic agent; Investigation; Laboratories; Laboratory Rat; Lateral; Life; Locales; Messenger RNA; Modeling; Mus; Nature; Neurons; Obesity; PPAR gamma; Patients; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phodopus sungorus; Prader-Willi Syndrome; Rattus; Recommendation; Rewards; Rodent; Rodent Model; Role; Running; Siberian Hamster; Site; Somatotropin; Source; Stomach; Structure of nucleus infundibularis hypothalami; System; Testing; Ventral Tegmental Area; base; combat; dopaminergic neuron; feeding; ghrelin; ghrelin receptor; improved; inhibitor/antagonist; innovation; mind control; neurochemistry; neuropeptide Y; novel; obesity prevention; obesity treatment; parabrachial nucleus; public health relevance; receptor; relating to nervous system; research study; rosiglitazone; ART protein; Acylation; Agonist; Animal Model; Animals; Automobile Driving; Behavior; Behavior Therapy; Belief; Body Weight decreased; Brain; Butyric Acids; Calories; Coenzyme A; Consumption; Diet; Disease; Eating; Endocrine; Fasting; Feeding behaviors; Figs - dietary; Fluorescent in Situ Hybridization; Food; Food deprivation (experimental); Genetic Engineering; Grant; Hamsters; Hereditary Disease; Home environment; Hormonal; Housing; Human; Hunger; Hyperphagia; Injection of therapeutic agent; Investigation; Laboratories; Laboratory Rat; Lateral; Life; Locales; Messenger RNA; Modeling; Mus; Nature; Neurons; Obesity; PPAR gamma; Patients; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phodopus sungorus; Prader-Willi Syndrome; Rattus; Recommendation; Rewards; Rodent; Rodent Model; Role; Running; Siberian Hamster; Site; Somatotropin; Source; Stomach; Structure of nucleus infundibularis hypothalami; System; Testing; Ventral Tegmental Area; base; combat; dopaminergic neuron; feeding; ghrelin; ghrelin receptor; improved; inhibitor/antagonist; innovation; mind control; neurochemistry; neuropeptide Y; novel; obesity prevention; obesity treatment; parabrachial nucleus; public health relevance; receptor; relating to nervous system; research study; rosiglitazone

DESCRIPTION (provided by applicant): Obesity is a life threatening disease with economically devastating consequences. Food intake (FI) reduction is the cornerstone for obesity treatment and has largely been unsuccessful. We offer an alternative approach- reducing food hoarding (FH) that thereby decreases stored foods thus decreasing the opportunities and increasing the efforts required to overeat. Most animals, including humans, hoard food. FH has morphed from a strategy to combat food scarcity into excessive external energy storage due to abundant, inexpensive, calorically-dense food, larger food storage units and improved food shelf lives - factors we believe significantly contribute to the human obesity increases. The most potent stimulator of FH is hunger exacerbating 'normal' food purchases by humans or foraged/hoarded food by rodents. Moreover, because ~85% of FI occurs at home and because obese store more calories per person than their lean counterparts, it is even easier for the obese to overeat. It's not surprising that a common recommendation for weight loss is reducing food stored at home. The innovation of this proposal lies with: 1) study of an unappreciated behavior --FH, 2) the novel animal model of human FH -- Siberian hamsters, a laboratory model that mimics FH in nature, 3) our unique housing system where hamsters earn food pellets to eat and hoard by wheel running, and 4) several approaches: fluorescent in situ hybridization, an unique inhibitor of ghrelin activation (GO-CoA-Tat) and tests of the role of brai peroxisome proliferator- activated receptor gamma (PPAR?) in FH. We hypothesize that a FH network is stimulated by FD causing increases in ghrelin secretion. Ghrelin stimulates neurons bearing ghrelin receptors [growth hormone secretagogue (GHSR)]. These include arcuate nucleus (Arc) AgRP/gamma-amino butyric acid (GABA) neurons and ventral tegmental area (VTA) dopamine (DA) neurons. Stimulation of their GHSRs increases PPAR? found therein. Finally, Arc AgRP neurons release AgRP at several terminal sites and GABA from their projections to the lateral parabrachial nucleus (LPBN) collectively stimulating FH. Our overarching hypothesis is that FD engages a distributed FH network with the hunger-released stomach peptide ghrelin a key initiator that interacts with several central sites and neurochemicals traditionally designated as controllers of FI and reward, as well as a virtually unexplored central factor, PPAR?. We will test this hypothesis in two Specific Aims 1: How does ghrelin initiate the persisting stimulation of FH? and What is role of AgRP neurons and brain PPAR? in the persisting increases in FH? Collectively, we will identify key components driving the prolonged FH increases deepening our understanding of this fundamental ingestive behavior of humans and rodents that we almost exclusively study. This will greatly impact behavioral or drug therapies for obesity and for the genetic disorder Prader-Willi-Syndrome characterized by obesity and uncontrollable FH.

描述（由申请人提供）：肥胖是一种威胁生命的疾病，具有经济上的毁灭性后果。食物摄入量（FI）减少是肥胖治疗的基石，在很大程度上没有成功。我们提供另一种方法，减少食物ho积（FH），从而减少了储存的食物，从而减少了机会并增加了暴饮暴食所需的努力。大多数动物，包括人类，ho积食物。 FH从一项策略中演变为将粮食稀缺性打击到过多的外部能源储存中，这是由于丰富，廉价，热量密集的食物，较大的食品储存单元和改善的食品架子的生活 - 我们认为因素会显着促进人类肥胖的增加。 FH最有效的刺激剂是饥饿加剧了人类或啮齿动物的觅食/ho积食物的“正常”食物。此外，由于〜85％的FI发生在家里，而且由于肥胖者每人的卡路里比瘦弱的同行储存的卡路里更多，所以肥胖太过吃饱了。不足为奇的是，减肥的常见建议是减少家里存储的食物。该提案的创新在于：1）研究不引人注意的行为-FH，2）人类FH的新型动物模型 - 西伯利亚仓鼠，一个模仿自然中FH的实验室模型，3）我们独特的住房系统，仓鼠在该系统中赢得了hamsters赢得乘坐方向盘饮食和ho积的食物，以及几个近距离的食物，以及4）杂种，一个独特的杂种，是一个独特的杂种，一个独特的杂种，一项独特的动态，并构成独特的态度， （GO-COA-TAT）和FH中Brai过氧化物酶体增殖物激活受体伽马（PPAR？）的作用的测试。我们假设FH网络受到FD的刺激，从而导致生长素释放素分泌的增加。生长素蛋白刺激含有生长素蛋白受体的神经元[生长激素促分泌素（GHSR）]。其中包括弧形核（ARC）AGRP/Gamma-Amino丁酸（GABA）神经元和腹侧对段区域（VTA）多巴胺（DA）神经元。刺激其GHSR会增加PPAR？在其中找到。最后，ARC AGRP神经元在几个末端位点释放AGRP，并从其投影释放到侧面和旁核核（LPBN），共同刺激FH。我们的总体假设是，FD与饥饿释放的胃肽生长素蛋白与一个关键引发剂相互作用，它与传统上指定为FI和奖励控制器的几个中心地点和神经化学物质相互作用，以及几乎没有开发的中心因素，PPAR？我们将在两个具体目标中检验这一假设1：生长素素如何启动FH的持续刺激？ AGRP神经元和脑PPAR的作用是什么？在FH持续增加？总体而言，我们将确定推动长期FH的关键组成部分，从而加深了我们几乎完全研究的人类和啮齿动物的这种基本摄入行为的理解。这将极大地影响肥胖症的行为或药物疗法，以及以肥胖和无法控制的FH为特征的遗传疾病Prader-Willi-syndrome。