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是不成功的。因为食物需要获得（觅食，即使是人类），并且经常被储存起来供以后食用（囤积在冰箱、冰柜里），这可能为药理学/行为干预提供了另一个攻击点，但觅食/囤积的潜在机制在很大程度上是未知的。饥饿的人和肥胖的人分别比健康的人和瘦弱的人带回家更多的食物和更高的脂肪/卡路里食物。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，在那里，它们运行规定次数的车轮旋转以获得食物颗粒，并发现饥饿的仓鼠也会带回家更多的食物，但与大多数动物不同的是，禁食后不会吃得过多；因此，喂食与觅食/囤积是分开的，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（SAs）中的神经化学/神经解剖学基础。我们的首要假设是，觅食/囤积在很大程度上是由几个厌氧和厌氧肽控制的，这些肽先前在实验室大鼠和小鼠中被证明会影响进食。我们将测试随着禁食而变化的外周和中枢肽，从而可能是剥夺引起的觅食/囤积增加的机制。在SA 1中，我们将测试饥饿素受体(R)拮抗剂是否阻断饥饿素诱导的觅食/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是否抑制禁食引起的增加觅食/囤积。我们将测试脂肪因子喂养抑制瘦素是否会抑制禁食引起的觅食/囤积增加。在SA 2中，我们将通过NPY-皂苷检测携带神经肽Y (NPY)-R的脑室旁核（PVN）神经元是否通过NPY-皂苷选择性免疫抑制禁食诱导的觅食/囤积增加，以及哪种NPY-R亚型在静脉注射NPY-R亚型拮抗剂诱导的禁食增加中起重要作用。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）是否会刺激随意觅食/囤积，以及每种受体亚型的拮抗作用是否会阻止禁食引起的增加觅食/囤积。在SA 3中，我们将测试共注射NPY和agouti相关蛋白是否会在阈下剂量共注射时出现这种情况。NPY和agouti相关蛋白在弓形神经元中共定位，随着禁食而增加，每一个都刺激觅食/囤积。由于弓形NPY/AgRP携带胃饥饿素- r的神经元可能是胃饥饿素诱导的食物摄入增加的基础，我们将测试通过静脉注射亚型拮抗剂阻断下游NPY- r是否会阻断胃饥饿素诱导的觅食/囤积增加。我们将测试PVN注射npy皂苷对下游NPY-Rs的破坏是否会阻止饥饿素引起的觅食/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.