Peptidergic Control of Appetitive Ingestive Behaviors

描述（由申请人提供）：肥胖是一种危及生命的疾病，具有经济上的破坏性后果。减少食物摄入（FI）是肥胖治疗的基石，但在很大程度上并不成功。我们提供了一种替代方法-减少食物囤积（FH），从而减少储存的食物，从而减少暴饮暴食的机会并增加所需的努力。大多数动物，包括人类，都会囤积食物。FH已经从一种对抗食物短缺的策略演变为过度的外部能量储存，这是由于丰富，廉价，热量密集的食物，更大的食物储存单元和更长的食物保质期-我们认为这些因素显著导致人类肥胖增加。FH最有效的刺激物是饥饿，这会加剧人类的“正常”食物购买或啮齿动物的觅食/囤积食物。此外，由于约85%的FI发生在家中，并且由于肥胖者比瘦的人储存更多的卡路里，因此肥胖者更容易暴饮暴食。这并不奇怪，减肥的一个常见建议是减少储存在家里的食物。该提案的创新在于：1）研究一种不受重视的行为-FH，2）人类FH的新型动物模型-西伯利亚仓鼠，一种模拟自然界FH的实验室模型，3）我们独特的住房系统，仓鼠通过车轮运行来赚取食物颗粒并囤积，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-达特）和脑过氧化物酶体增殖物激活受体γ（PPARγ）在FH中的作用的测试。我们假设FH网络是由FD刺激引起生长激素释放肽分泌增加。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GHSRs增加其中发现的PPARγ。最后，Arc AgRP神经元释放AgRP在几个终端网站和GABA从他们的投射到外侧臂旁核（LPBN）集体刺激FH。我们的总体假设是，FD与饥饿释放的胃肽ghrelin（一种关键的引发剂）形成了一个分布式FH网络，该网络与几个中心位点和传统上被指定为FI和奖励控制器的神经化学物质以及一个几乎未被探索的中心因子PPARγ相互作用。我们将在两个特定的目标1：如何饥饿素启动持续刺激FH的这一假设进行测试？AgRP神经元和脑内PPARγ在FH持续增加中的作用是什么？总的来说，我们将确定驱动长期FH增加的关键成分，加深我们对人类和啮齿动物这种基本摄食行为的理解，我们几乎只研究这些行为。这将极大地影响肥胖症和以肥胖和不可控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 (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.