Neurobiological controls of hyperphagia in obesity

肥胖症吞咽过多的神经生物学控制

• 批准号: 6706773
• 负责人: ANTHONY V AZZARA
• 金额: $ 11.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706773
• 关键词: appetite; appetite regulatory center; behavior test; behavioral genetics; biological signal transduction; genetic susceptibility; genetically modified animals; hypothalamus; laboratory mouse; laboratory rat; leptin; neurochemistry; neuropeptide Y; neurophysiology; neuropsychological tests; nutrient intake activity; obesity; overeating; receptor expression; sensory feedback

DESCRIPTION (provided by applicant): The overall objective of the proposed research is to determine the contribution of endogenous hypothalamic NPY in the hyperphagia in obesity prone species. During the career award, the candidate will learn: 1) neurophysiological techniques to record from the central nervous system of the anesthetized rat and, 2) how to apply physiological genomics to the study of ingestive behavior. This multidisciplinary training will advance the candidate's career goal to become an independent research scientist. Experiments will be conducted at the Bourne Laboratory (White Plains, NY) with Dr. Gary Schwartz, an expert in neurophysiological evaluation of sensory controls of food intake, as the primary mentor. Dr. Streamson Chua, Columbia University, will be a co-mentor, and he will provide training in physiological genomics and availability of transgenic leptin receptor rescues and inducible leptin receptor knock-out mutations. NPY has been proposed to increase feeding by increasing appetitive behaviors that precede and facilitate contact with food. Consistent with this hypothesis, we have shown that NPY dramatically increases instrumental responding for food in rats and mice. We also find that NPY only weakly stimulates instrumental responding when food is not available. These data suggest that signals arising from food stimuli are critical in NPY's ability to promote instrumental responding for food. In the proposed studies, we will perform behavioral and brainstem neurophysiological experiments designed to elucidate the neurochemical and genetic basis of hyperphagia in obesity prone rodents with leptin-signalling deficits. We will test the following 2 hypotheses: 1) Exogenous central NPY promotes instrumental responding for food by increasing the behavioral and neurophysiological potency of orosensory food stimuli, and, 2) Upregulation of endogenous hypothalamic NPY in hyperphagic genetic rodent models with leptin signalling deficits mediates increased instrumental responding to obtain food. We will evaluate instrumental responding for food after manipulating endogenous hypothalamic NPY levels in transgenic mouse models with leptin signalling deficits by: 1) replacing leptin, or 2) by altering the expression of leptin receptors. Results from these studies will help to reveal the contribution of endogenous hypothalamic NPY in the hyperphagia in obesity prone species.

描述（由申请人提供）： 拟议的研究的总体目标是确定内源性下丘脑NPY在肥胖物种中肥大中的贡献。在职业奖中，候选人将学习：1）从麻醉大鼠的中枢神经系统中记录的神经生理技术，以及2）如何将生理基因组学应用于摄入行为的研究。这种多学科的培训将促进候选人的职业目标，成为一名独立的研究科学家。实验将在Bourne实验室（纽约州怀特普莱恩斯）与Gary Schwartz博士（神经生理学评估食物摄入的感觉控制）的专家Gary Schwartz博士进行。哥伦比亚大学的Streamson Chua博士将是一名院长，他将提供有关生理基因组学的培训以及转基因瘦素受体营救和可诱导的瘦素受体敲除突变的培训。已经提出，NPY通过增加和促进与食物接触之前的食欲行为来增加进食。与这一假设一致，我们已经表明，NPY急剧增加了对大鼠和小鼠食物的工具反应。我们还发现，在没有食物时，NPY只会刺激器械响应。这些数据表明，食物刺激引起的信号对于NPY促进食物的工具反应的能力至关重要。在拟议的研究中，我们将进行行为和脑干神经生理实验，旨在阐明肥胖的肥胖啮齿动物的神经化学和遗传学基础，具有瘦素信号缺陷。我们将测试以下2个假设：1）外源性中央NPY通过增加口感食物刺激的行为和神经生理学效力，促进食物的仪器反应，以及2）上源性下丘脑下丘脑NPY在多态植物啮齿动物模型中使用LeptIts Signering NebertIts NebertIts MediciateS助长了食品，从而增加了食物，从而增加了食物。我们将在通过瘦素信号传导缺陷的转基因小鼠模型中操纵内源性下丘脑NPY水平后评估食物的仪器反应：1）通过改变瘦素受体的表达来代替瘦素。这些研究的结果将有助于揭示内源性下丘脑NPY在肥胖物种中肥大中的贡献。