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方面基本上不成功。由于食物必须获得（觅食，即使在人类中），并且通常被储存以供以后消费（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更多的食物和更高的脂肪/热量的食物比他们饱和瘦的同行，分别。我们在西伯利亚仓鼠中开发了一种新的人类觅食/囤积模型，在那里它们运行规定数量的车轮旋转以获得食物颗粒，并发现饥饿的仓鼠也带回家更多的食物，但与大多数动物不同，禁食后不会吃得过多;因此喂食与觅食/囤积分开，使它们成为理想的受试者。这里的总体目的是测试这些食欲行为（觅食/囤积）的神经化学/神经解剖学基础。我们的总体假设是，觅食/囤积在很大程度上是由几个orexigenic和orexigenic肽先前在实验室大鼠和小鼠影响喂养。我们将测试外周和中枢肽的变化与禁食，因此可能是潜在的剥夺引起的觅食/囤积增加的机制。在SA 1中，我们将测试ghrelin受体（R）拮抗剂是否阻断禁食和ghrelin诱导的觅食/囤积增加。我们将测试胆囊收缩素（CCK），一种已知的饱腹感肽，是否通过给予选择性CCK-R拮抗剂来抑制随意觅食/囤积，以及系统性CCK是否抑制禁食诱导的觅食/囤积增加。我们将测试脂肪因子摄食抑制剂瘦素是否抑制禁食诱导的觅食/囤积增加。在SA 2中，我们将测试通过NPY-皂草素选择性免疫损伤神经肽Y（NPY）-R的室旁核（PVN）神经元是否阻断禁食诱导的觅食/囤积增加，以及通过icv注射NPY-R亚型拮抗剂，哪种NPY-R亚型对禁食诱导的增加是重要的。我们将测试icv注射食欲素A或B（与活动和食物摄入有关的肽）是否刺激随意觅食/囤积，以及每种受体亚型的拮抗作用是否阻断禁食诱导的觅食/囤积增加。在SA 3中，我们将测试当以亚阈值剂量共注射时，共注射在弓状神经元中共定位的NPY和刺豚鼠相关蛋白、随着禁食增加并且各自刺激觅食/囤积是否会这样做。由于弓形NPY/AgRP ghrelin-R轴承神经元可能是ghrelin诱导的食物摄入量增加的基础，我们将测试通过icv注射亚型拮抗剂阻断下游NPY-R是否阻断ghrelin诱导的觅食/囤积增加。我们将测试通过PVN注射NPY-皂草素是否破坏下游NPY-Rs阻断ghrelin诱导的觅食/囤积增加。

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.