Grhelin, NPY/Agrp Neurons, and Meal Initiation

Grhelin、NPY/Agrp 神经元和进餐开始

• 批准号: 6844974
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844974
• 关键词: appetite regulatory center; behavioral /social science research tag; bioenergetics; biological signal transduction; data collection methodology /evaluation; gastrointestinal hormones; gene expression; hormone receptor; hormone regulation /control mechanism; hypothalamus; insulin; laboratory mouse; leptin; neurons; neuropeptide Y; nutrient intake activity; nutrition related tag; obesity; phenotype; weight control

Body weight regulation involves adjustments in food intake that compensate for fluctuations in energy stores. These adjustments are comprised of alterations in meal number, size, or both. Compared with the well understood systems that regulate meal termination, and thus, meal size, those that regulate meal initiation and frequency remain enigmatic. The recently discovered enteric hormone, ghrelin, is implicated in the cascade of events leading to meal initiation, but evidence favoring this assertion is largely circumstantial. We propose to test critically the requirement for ghrelin and its most well established CNS target - NPY/Agrp neurons - in meal initiation, using loss-of-function experiments. We will address the following broad questions. (1) Is ghrelin signaling required for normal meal initiation, meal termination, or both? Using state-of-the art equipment to measure food intake continuously on a second-to-second basis, we will assess the effect on meal number, size, and duration, of novel, highly potent antagonists of the ghrelin receptor (GHS-R), at doses that decrease overall food intake. Experiments will be conducted on ad libitum-fed mice as well as those subjected to a variety of acute and chronic states of energy deficit that challenge meal-initiation signals. We will study wild-type and GHS-R /- mice in parallel, both to verify that the anorectic effects of GHS-R antagonists result specifically from blockade of the GHS-R, and also to compare the effects of complementary pharmacologic and genetic ablation of GHS-R signaling. (2) Are NPY/Agrp neurons required for normal meal initiation, energy homeostasis, and response to ghrelin? Our co-investigator, Dr. Greg Barsh, has created mice in which NPY/Agrp neurons are gradually and continuously destroyed in adulthood. The animals are a valuable resource to determine the requirement for NPY/Agrp neurons in each of ghrelin's known anabolic actions, as well as to assess the role of NPY/Agrp neurons themselves in meal patterning and overall energy homeostasis. We propose a thorough phenotyping analysis of these mice to address these issues. (3) Do intracellular signaling events triggered by ghrelin in key hypothalamic neurons - especially NPY/Agrp neurons - oppose those triggered by leptin and insulin (and vice versa)? Together, these studies have the potential to fundamentally advance our understanding of feeding biology at the molecular, cellular, and behavioral level.

体重调节涉及食物摄入量的调整，以补偿能量储存的波动。这些调整包括膳食数量、份量或两者的改变。与众所周知的调节进餐终止和进餐量的系统相比，那些调节进餐开始和频率的系统仍然是个谜。 最近发现的肠道激素胃饥饿素与导致进餐的一系列事件有关，但支持这一主张的证据很大程度上是间接的。我们建议使用功能丧失实验来严格测试进餐开始时对 ghrelin 及其最完善的 CNS 靶点 - NPY/Agrp 神经元的需求。我们将解决以下广泛问题。 (1) 正常进餐开始、进餐终止或两者都需要生长素释放肽信号传导吗？使用最先进的设备每秒连续测量食物摄入量 在此基础上，我们将评估新型高效生长素释放肽受体 (GHS-R) 拮抗剂在减少总体食物摄入量的剂量下对进餐次数、大小和持续时间的影响。实验将在随意喂养的小鼠以及那些遭受各种急性和慢性能量缺乏状态的小鼠身上进行，这些能量缺乏状态会挑战进餐开始信号。 我们将同时研究野生型和 GHS-R /- 小鼠，以验证 GHS-R 拮抗剂的厌食作用是由 GHS-R 阻断引起的，并比较 GHS-R 信号传导的互补药理学和遗传消除的效果。 (2) 正常进餐开始、能量稳态和对生长素释放肽的反应是否需要 NPY/Agrp 神经元？我们的合作研究员 Greg Barsh 博士创造了 NPY/Agrp 小鼠 神经元在成年期逐渐且持续地被破坏。这些动物是宝贵的资源，可用于确定 NPY/Agrp 神经元在每种已知的 ghrelin 合成代谢作用中的需求，以及评估 NPY/Agrp 神经元本身在膳食模式和整体能量稳态中的作用。我们建议对这些小鼠进行彻底的表型分析来解决这些问题。 (3) ghrelin 是否触发细胞内信号事件 关键的下丘脑神经元 - 特别是 NPY/Agrp 神经元 - 对抗瘦素和胰岛素触发的神经元（反之亦然）？总之，这些研究有可能从根本上增进我们对分子、细胞和行为水平上的喂养生物学的理解。