Peptidergic Control of Appetitive Ingestive Behaviors

食欲摄取行为的肽能控制

• 批准号: 7251031
• 负责人: Timothy Jon Bartness
• 金额: $ 29.62万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251031
• 关键词: Peptidergic; Control; Appetitive; Ingestive; Behaviors

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.

描述（由申请人提供）：目前着重于减少食物摄入的方法在很大程度上没有成功地治疗肥胖症。由于必须获取食物（甚至在人类中觅食），并且经常存储以供以后的食用（在冰箱中ho积，冰柜），这可能会为药理/行为干预提供另一个攻击点，但在很大程度上尚不清楚觅食/ho积的机制。饥饿和肥胖的人类分别比他们的饮食和瘦肉更高的食物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开发了一种新颖的人类觅食/ho积模型，在那里他们经营着规定的车轮旋转量来赚取食物颗粒，发现饥饿的仓鼠还带回了更多的食物，但与大多数动物不同，速度不太过分。因此，喂食与觅食/ho积使他们成为理想的主题。这里的总体目的是测试这些食欲行为（觅食/ho积）的神经化学/神经解剖学基础（SAS）。我们的总体假设是，觅食/ho积在很大程度上受到实验室大鼠和小鼠以前显示的几种甲状腺素和厌食肽，以影响进食。我们将测试随禁食而变化的外围和中央肽，因此可能是剥夺引起的觅食/ho积的增加的机制。在SA 1中，我们将测试生长素蛋白受体（R）拮抗作用是否会阻止禁食和ghrelin诱导的觅食/ho积增加。我们将测试已知的饱腹肽（CCK）是否通过给出选择性的CCK-R拮抗剂以及全身性CCK是否抑制禁食引起的增加的觅食/ho积。我们将测试脂肪因子喂养抑制剂瘦素是否抑制禁食引起的觅食/ho积增加。在SA 2中，我们将测试神经肽Y（NPY）-R轴承核核（PVN）神经元是否通过NPY-骨蛋白阻滞进行禁食诱导的增加的觅食/ho饲/hoarding的神经元，而NPY-R子类型的增加对于禁食诱导的NPY-REXTINS npy-Regations subtagotions的npy-r子类型很重要。我们将测试ICV注射Orexin A或B的注射，与活动和食物摄入有关的肽，刺激自发觅食/ho积，以及每个受体亚型的拮抗作用是否会阻止禁食会诱导的增加的觅食/ho积。在SA 3中，我们将测试在弧形神经元中共定位的NPY和Agouti相关蛋白的共同注射，随着禁食的增加并刺激觅食/ho积时，在亚阈值以亚急性剂量注入时会这样做。由于ARCAURE NPY/AGRP GHRELIN-R轴承神经元可能是生长素素诱导的食物摄入量增加的基础，因此我们将测试通过ICV注射亚型拮抗剂对下游NPY-RS的封锁，阻断了Ghrelin诱导的增加的饲料/ho积。我们将通过PVN注入NPY-淀粉蛋白阻断Ghrelin诱导的增加的觅食/ho饲剂来测试下游NPY-RS的破坏。