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（由申请人提供）：了解能量平衡和体重调节需要了解与控制膳食中食物摄入有关的口腔和口腔后感觉信号的行为和神经评价，以及与储存燃料的可用性有关的信号。肥胖代表能量平衡的一种重要的功能失调状态，并且经常伴随着表现为膳食量增加的摄食过多。肥胖的两种小鼠模型，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，也是过度吞噬的，并且相对于野生型瘦对照表现出增加的膳食量而没有改变的膳食频率。在拟议的研究中，我们概述了行为和免疫细胞化学研究，旨在阐明瘦素信号传导的作用，确定在肥胖症的摄入口和口后感官的影响。这些实验将：1）表征口腔和上消化道（GI）食物刺激物影响膳食中食物摄入的能力，2）评估遗传性瘦素信号传导缺陷在控制膳食量中干扰口腔和上GI信号的反馈效力的程度，和3）描述了由口服和胃肠道刺激物激发的中枢神经系统激活的模式，这些刺激物影响瘦素信号传导改变的小鼠的进食量。我们将重点关注C57 B6 J小鼠作为这些研究的背景品系，因为：1）它具有良好的饮食性肥胖倾向，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ob/ob小鼠中口服和GI食物刺激的反馈效力的能力，2）LEPR-B的转基因神经元特异性替代恢复db/db小鼠中口服和GI食物刺激的正常处理的能力，和3）中枢与外周可诱导的LEPR-B缺乏对小鼠进食的影响。为了确定中枢神经元区域的重要瘦素的能力，调节处理的食物刺激，我们也将评估中枢神经系统模式的c-Fos的表达在这些菌株在选择性的口服和/或胃肠道食物刺激。这种系统的评估与膳食有关的刺激，其中枢神经代表，并与能量平衡肽信号的整合将显着推进我们的理解的神经-体液相互作用的代谢控制的食物摄入。