Peptidergic Control of Appetitive Ingestive Behaviors

食欲摄取行为的肽能控制

• 批准号: 8815294
• 负责人: Bingzhong Xue
• 金额: $ 32.19万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815294
• 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; Compulsive Hoarding; Consumption; Diet; Disease; Eating; Endocrine; Fasting; Feeding behaviors; Figs - dietary; Fluorescent in Situ Hybridization; Food; Food deprivation (experimental); Genetic Engineering; Grant; Hamsters; Health; Hereditary Disease; Home environment; Hormonal; Housing; Human; Hunger; Hyperphagia; Injection of therapeutic agent; Investigation; Laboratories; Laboratory Rat; Laboratory mice; Lateral; Life; Locales; Messenger RNA; Modeling; Mus; Nature; Neurons; Obesity; PPAR gamma; Patients; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phodopus sungorus; Prader-Willi Syndrome; Prevention therapy; 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; 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 (PPARγ) 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 PPARγ 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, PPARγ. 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 PPARγ 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）：肥胖是一种危及生命的疾病，会带来严重的经济后果。减少食物摄入量 (FI) 是肥胖治疗的基石，但在很大程度上并未成功。我们提供了一种替代方法，从而减少了食物囤积 (FH)。减少储存的食物，从而减少了储存食物过多的机会并增加了储存食物的努力，包括人类在内，储存食物的策略已经从一种应对食物短缺的策略转变为过度的外部能量储存。热量密集的食物、更大的食物储存单位和延长的食物保质期——我们认为，导致人类肥胖增加的最有力的因素是饥饿，加剧了人类“正常”食物的购买或啮齿类动物觅食/囤积的食物。此外，由于约 85% 的 FI 发生在家里，而且肥胖者每人储存的卡路里比瘦体重的卡路里更多，因此肥胖者更容易吃得过多。减肥的常见建议是减少储存的食物，这并不奇怪。该提案的创新之处在于：1）研究一种不被重视的行为——FH，2）人类FH的新颖动物模型——西伯利亚仓鼠，一种模仿自然界FH的实验室模型，3）我们独特的住房系统。仓鼠通过轮子奔跑获得食物颗粒供食用和储藏，以及 4) 几种方法：荧光原位杂交、生长素释放肽激活的独特抑制剂 (GO-CoA-Tat) 以及测试FH 中的 brai 过氧化物酶体增殖物激活受体 γ (PPARγ) 我们发现 FD 刺激 FH 网络，导致生长素释放肽 (Ghrelin) 刺激带有生长素释放肽受体 [生长激素促分泌素 (GHSR)] 的神经元。 ) AgRP/γ-氨基丁酸 (GABA) 神经元和腹侧被盖区 (VTA) 多巴胺 (DA) 神经元。刺激 GHSR 会增加其中的 PPARγ，最后，Arc AgRP 神经元在几个末端位置释放 AgRP，并从其向臂旁核 (LPBN) 的投射中释放 GABA，共同刺激 FH。饥饿释放胃肽 ghrelin 是一种关键的引发剂，与几个中枢部位和传统上被指定为 FI 和奖励控制者的神经化学物质相互作用，并且实际上是一种我们将在两个具体目标 1 中检验这一假设：ghrelin 如何启动 FH 的持续刺激？以及 AgRP 神经元和大脑 PPARγ 在 FH 持续增加中的作用是什么？驱动长期 FH 的成分的增加加深了我们对人类和啮齿动物这种基本摄入行为的理解，我们几乎专门研究这一行为，这将极大地影响肥胖和遗传性疾病的行为或药物治疗。普瑞德威利综合征的特征是肥胖和无法控制的 FH。