Peptidergic Control of Appetitive Ingestive Behaviors

描述(申请人提供)：肥胖是一种危及生命的疾病，具有破坏性的经济后果。减少食物摄入量(FI)是肥胖治疗的基石，但在很大程度上并不成功。我们提供了另一种方法-减少囤积食物(FH)，从而减少储存的食物，从而减少暴饮暴食的机会和增加所需的努力。大多数动物，包括人类，都会囤积食物。FH已经从对抗食品稀缺的战略演变为过度的外部能量储存，这是由于丰富、廉价、高热量的食品、更大的食品储存单位和更长的食品保质期-我们认为这些因素对人类肥胖的增加有重要贡献。FH最有力的刺激物是饥饿，它会加剧人类“正常”的食物购买或啮齿动物的觅食/囤积食物。此外，由于大约85%的FI发生在家里，而且肥胖的人比瘦的人储存了更多的卡路里，肥胖者更容易暴饮暴食。一个常见的减肥建议是减少储存在家里的食物，这并不令人惊讶。这一建议的创新之处在于：1)对一种未知的行为进行研究--FH，2)人类FH的新动物模型--西伯利亚仓鼠，这是一个模拟自然界FH的实验室模型，3)我们独特的住房系统，仓鼠通过轮子跑来赚取食物颗粒吃和囤积，以及4)几种方法：荧光原位杂交，一种独特的Ghrelin激活抑制剂(GO-CoA-TAT)和测试脑过氧化酶体增殖物激活受体伽马(PPAR？)的作用。在FH。我们假设FH网络是由FD刺激的，导致Ghrelin分泌增加。Ghrelin刺激带有Ghrelin受体的神经元[生长激素促分泌素(GHSR)]。这些神经元包括弓状核(Arc)、AgRP/γ-氨基丁酸(GABA)神经元和腹侧被盖区(VTA)多巴胺(DA)神经元。刺激他们的GHSR会增加PPAR？在里面找到的。最后，Arc AgRP神经元在几个终末位置释放AgRP，并从其向臂旁外侧核(LPBN)的投射中释放GABA，共同刺激FH。我们的总体假设是，FD参与了一个分布的FH网络，饥饿释放的胃肽ghrelin是一个关键的启动者，它与几个中枢部位和神经化学物质相互作用，传统上被认为是FI和奖励的控制器，以及一个几乎未被探索的中央因子PPAR？我们将在两个特定的目标1中检验这一假说：Ghrelin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的持续增长中？总而言之，我们将确定推动FH延长增长的关键因素，加深我们对人类和啮齿动物这一基本摄食行为的理解，我们几乎只研究这一行为。这将极大地影响对肥胖和以肥胖和无法控制的FH为特征的遗传性疾病Prader-Willi综合征的行为或药物治疗。

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.