Sensory Controls of Hyperphagia in Obesity

描述（由申请人提供）：了解能量平衡和体重调节需要了解控制膳食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相关的信号。肥胖代表了一种重要的能量平衡功能失调状态，并且经常伴有食欲亢进，表现为膳食量增加。两种肥胖小鼠模型，即缺乏瘦素的 ob/ob 小鼠和缺乏功能性瘦素受体 (LEPR-B) 的 db/db 小鼠，也是食量过多的，并且与野生型瘦对照相比，在不改变进餐频率的情况下表现出进食量增加。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在确定口腔和口腔后感觉对肥胖摄入的影响中的作用。这些实验将：1）表征口腔和上消化道（GI）食物刺激影响膳食摄入量的能力，2）评估遗传性瘦素信号传导缺陷干扰口腔和上消化道信号在控制膳食量方面的反馈效力的程度，以及3）表征由口腔和胃肠道刺激激发的中枢神经系统激活模式，这些刺激影响瘦素信号改变的小鼠的膳食量。我们将重点关注 C57B6J 小鼠作为这些研究的背景品系，因为：1) 它具有明确的饮食肥胖倾向，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ob/ob小鼠口腔和胃肠道食物刺激反馈效力的能力，2）LEPR-B的转基因神经元特异性替代恢复db/db小鼠口腔和胃肠道食物刺激正常处理的能力，以及3）中枢性与外周性诱导性LEPR-B缺陷对小鼠进食的影响。为了确定瘦素调节食物刺激处理能力的重要中枢神经元区域，我们还将评估这些菌株中 c-Fos 表达响应选择性口腔和/或胃肠道食物刺激的中枢神经系统模式。这种对与膳食相关的刺激、它们的中枢神经表征以及它们与能量平衡肽信号的整合的系统评估将显着增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.