Sensory Controls of Hyperphagia in Obesity

描述（由申请人提供）：理解能量平衡和体重调节需要理解口腔和口腔后感觉信号的行为和神经评估，这些信号参与控制一餐中的食物摄入，以及与储存燃料的可用性相关的信号。肥胖是一种重要的能量平衡失调状态，经常伴有食性过多，表现为食量增加。两种肥胖小鼠模型，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，也有贪食现象，与野生型瘦对照相比，它们的食量增加，但进餐频率不变。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服和口服后对摄入的感觉影响中的作用。这些实验将：1)表征口服和上消化道（GI）食物刺激对餐内食物摄入的影响；2)评估遗传瘦素信号缺乏对控制餐量的口服和上消化道信号反馈效能的干扰程度；3)表征瘦素信号改变的小鼠在口服和胃肠道刺激影响餐量时中枢神经系统激活的模式。我们将重点关注C57B6J小鼠作为这些研究的背景菌株，因为：1)它具有良好的饮食肥胖倾向，2)它是ob/ob和db/db小鼠的背景菌株。我们将评估：1)瘦素改变ob/ob小鼠口服和胃肠道食物刺激反馈效能的能力，2)转基因神经元特异性替代LEPR-B恢复db/db小鼠口服和胃肠道食物刺激正常加工的能力，以及3)中枢与外周诱导的LEPR-B缺乏对小鼠进食的影响。为了确定瘦素调节食物刺激处理能力的重要中枢神经区域，我们还将评估这些菌株对选择性口服和/或胃肠道食物刺激的中枢神经系统c-Fos表达模式。这项对食物相关刺激、其中枢神经表征及其与能量平衡肽信号的整合的系统评估，将极大地促进我们对食物摄入代谢控制中神经-体液相互作用的理解。

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.