Sensory Controls of Hyperphagia in Obesity

肥胖症患者食欲过盛的感觉控制

• 批准号: 7027702
• 负责人: GARY J SCHWARTZ
• 金额: $ 32.29万
• 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: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027702
• 关键词: appetite regulatory center; behavior test; bioenergetics; biological signal transduction; body weight; genetically modified animals; immunocytochemistry; laboratory mouse; leptin; neural transmission; nutrient intake activity; nutrition related tag; obesity; overeating; sensory mechanism

DESCRIPTION (provided by applicant): Understanding energy balance and body weight regulation requires an understanding of the behavioral and neural evaluation of the oral and post-oral sensory signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Obesity represents an important dysfunctional state of energy balance, and is frequently accompanied by hyperphagia that is manifested by increased meal size. Two mouse models of obesity, the ob/ob mouse lacking leptin, and the db/db mouse, lacking functional leptin receptors (LEPR-B), are also hyperphagic, and exhibit increased meal size without altered meal frequency relative to wild type lean controls. In the proposed studies, we outline behavioral and immunocytochemical studies designed to elucidate the role of leptin signaling in determining the oral and post-oral sensory influences on ingestion in obesity. These experiments will: 1) characterize the ability of oral and upper gastrointestinal (GI) food stimuli to affect food intake within a meal, 2) assess the degree to which genetic leptin signaling deficiency interferes with the feedback potency of oral and upper GI signals in the control of meal size, and 3) characterize the patterns of central nervous system activation excited by oral and GI stimuli that affect meal size in mice with alterations in leptin signaling. We will focus on the C57B6J mouse as the background strain for these studies because: 1) it is has a well-described tendency toward dietary obesity and, 2) it is the background strain for ob/ob and db/db mice. We will evaluate: 1) the ability of leptin to modify the feedback potency of oral and GI food stimuli in ob/ob mice, 2) the ability of transgenic neuron-specific replacement of LEPR-B to restore normal processing of oral and GI food stimuli in db/db mice, and 3) the effect of central vs. peripheral inducible LEPR-B deficiency on eating in mice. To identify central neuronal regions important in leptin's ability to modulate the processing of food stimuli, we will also evaluate the central nervous system patterns of c-Fos expression in these strains in response to selective oral and/or GI food stimuli. This systematic assessment of meal-related stimuli, their central neural representation, and their integration with energy balance peptide signals will significantly advance our understanding of neuro-humoral interactions in the metabolic control of food intake.

描述(申请人提供)：要了解能量平衡和体重调节，需要了解控制一餐中食物摄入量的口腔和口腔后感觉信号的行为和神经评估，以及与储存燃料的可用性有关的信号。肥胖代表着一种重要的能量平衡失调状态，并经常伴随着吞噬功能亢进，表现为进食量增加。两种肥胖的小鼠模型，缺乏瘦素的ob/ob小鼠和缺乏功能性瘦素受体(LEPR-B)的db/db小鼠也是肥胖症小鼠，与野生型瘦肉对照相比，它们表现出进食增加而进食频率没有改变。在拟议的研究中，我们概述了行为和免疫细胞化学研究，旨在阐明瘦素信号在确定口腔和口腔后感觉对肥胖摄取的影响中所起的作用。这些实验将：1)表征口服和上胃肠道(GI)食物刺激影响一餐中食物摄入量的能力，2)评估遗传瘦素信号缺陷在多大程度上干扰口服和上胃肠道信号在控制膳食大小方面的反馈效力，以及3)表征由口服和GI刺激所激发的中枢神经系统激活模式，这些模式影响瘦素信号变化的小鼠的膳食大小。我们将重点关注C57B6J小鼠作为这些研究的背景品系，因为：1)它有很好的饮食肥胖倾向，2)它是ob/ob和db/db小鼠的背景品系。我们将评估：1)瘦素改变肥胖/肥胖小鼠口服和胃肠道食物刺激反馈能力的能力，2)转基因神经元特异性替代LEPR-B恢复db/db小鼠口腔和胃肠道食物刺激正常加工的能力，以及3)中枢和外周诱导性LEPR-B缺陷对小鼠进食的影响。为了确定在瘦素调节食物刺激处理能力中重要的中枢神经元区域，我们还将评估这些菌株对选择性口服和/或GI食物刺激的反应中中枢神经系统c-Fos表达的模式。这种对膳食相关刺激的系统评估，它们的中枢神经表征，以及它们与能量平衡肽信号的整合，将极大地促进我们对神经-体液相互作用在食物摄入量的代谢控制中的理解。