Peptidergic Control of Appetitive Ingestive Behaviors

描述(由申请人提供)：目前专注于减少食物摄入的方法在治疗肥胖症方面基本上是不成功的。由于食物必须被获取(觅食，甚至在人类中也是如此)，并且通常被储存起来供以后消费(囤积在冰箱、冰柜中)，这可能为药物/行为干预提供另一个攻击点，但觅食/囤积的机制在很大程度上是未知的。饥饿和肥胖的人带回家的食物和高脂肪/卡路里的食物分别比吃饱和瘦的人多。我们在西伯利亚仓鼠身上开发了一种新的人类觅食/囤积模型，在这种模式下，它们运行规定的轮子旋转来获得食物颗粒，并发现饥饿的仓鼠也会带回更多的食物，但与大多数动物不同的是，它们在禁食后不会暴饮暴食；因此，觅食与觅食/囤积分开，这使它们成为理想的研究对象。这里的总体目的是测试这些食欲行为(觅食/囤积)在三个特定目标(SA)上的神经化学/神经解剖学基础。我们的主要假设是，觅食/囤积在很大程度上是由几种以前在实验室大鼠和小鼠中显示的影响摄食的食欲素和厌氧肽控制的。我们将测试外周和中枢肽随着禁食而变化，从而可能是剥夺诱导觅食/囤积增加的潜在机制。在SA 1中，我们将测试Ghrelin受体(R)拮抗剂是否能阻止禁食和Ghrelin诱导的觅食/囤积增加。我们将测试已知的饱腹肽CCK是否通过给予选择性CCK-R拮抗剂来抑制随意觅食/囤积，以及全身性CCK是否抑制禁食诱导的更多觅食/囤积。我们将测试脂肪因子喂养抑制剂瘦素是否能抑制禁食诱导的更多的觅食/囤积。在SA 2中，我们将测试神经肽Y受体(NPY-R)神经元通过NPY-Saporin选择性免疫抑制是否阻断禁食引起的觅食/囤积增加，以及哪个NPY-R亚型在侧脑室注射NPY-R亚型拮抗剂引起的禁食增加中起重要作用。我们将测试脑室注射食欲素A或B，与活动和食物摄取有关的多肽，是否刺激自由觅食/囤积，以及每个受体亚型的拮抗是否阻止禁食诱导的觅食/囤积增加。在SA 3中，我们将测试共同注射在弓状神经元中的NPY和刺鼠相关蛋白是否会随着禁食和各自刺激觅食/囤积而增加，当联合注射阈值以下剂量时，是否会这样做。因为弓状的NPY/AgRP Ghrelin-R神经元可能是Ghrelin引起的食物摄取增加的基础，我们将测试侧脑室注射亚型拮抗剂阻断NPY-R下游是否阻断Ghrelin引起的觅食/囤积增加。我们将测试通过PVN注射NPY-Saporin破坏下游NPY-Rs是否阻断Ghrelin诱导的更多的觅食/囤积。

DESCRIPTION (provided by applicant): Current approaches focusing on curtailing food intake have largely been unsuccessful in treating obesity. Because food has to be acquired (foraging, even in humans) and often is stored for later consumption (hoarding in refrigerators, freezers), this could provide another point of attack for pharmacological/behavioral intervention, but the mechanisms underlying foraging/hoarding largely are unknown. Hungry and obese humans bring home more food and higher fat/calorie food than their sated and lean counterparts, respectively. We developed a novel model of human foraging/hoarding in Siberian hamsters, where they run a prescribed number of wheel revolutions to earn food pellets and found that hungry hamsters also bring home more food, but unlike most animals, do not overeat post-fast; thus feeding is separated from foraging/hoarding making them ideal subjects. The overall purpose here is to test for the neurochemical/neuroanatomical basis of these appetitive behaviors (foraging/hoarding) across three Specific Aims (SAs). Our overarching hypothesis is that foraging/hoarding largely are governed by several orexigenic and anorexigenic peptides shown previously in laboratory rats and mice to affect feeding. We will test peripheral and central peptides that change with fasting and thus may be mechanisms underlying deprivation-induced increases in foraging/hoarding. In SA 1, we will test whether ghrelin receptor (R) antagonism blocks fasting-and ghrelin-induced increases in foraging/hoarding. We will test whether cholecystokinin (CCK), a known satiety peptide, inhibits ad libitum foraging/hoarding by giving selective CCK-R antagonists and whether systemic CCK inhibits fasting-induced increased foraging/hoarding. We will test whether the adipokine feeding suppressant leptin, inhibits fasting-induced increased foraging/hoarding. In SA 2, we will test whether selective immunolesioning of neuropeptide Y (NPY)-R bearing paraventricular nucleus (PVN) neurons via NPY-saporin blocks fasting-induced increased foraging/hoarding and which NPY- R subtype is important for fasting-induced increases by icv injections of NPY-R subtype antagonists. We will test whether icv injections of orexin A or B, peptides implicated in activity and food intake, stimulate ad libitum foraging/hoarding and whether antagonism of each receptor subtype blocks fasting-induced increased foraging/hoarding. In SA 3, we will test whether co-injection of NPY and agouti-related protein that co-localize in arcuate neurons, increase with fasting and each stimulates foraging/hoarding, will do so when co-injected at subthreshold doses. Because arcuate NPY/AgRP ghrelin-R bearing neurons likely underlie ghrelin-induced increased food intake, we will test whether blockade of downstream NPY-Rs by icv injections of subtype antagonists block ghrelin-induced increased foraging/hoarding. We will test whether destruction of downstream NPY-Rs by PVN injection of NPY-saporin blocks ghrelin-induced increased foraging/hoarding.