Neural Substrates of Peptide Induced Satiety

描述（由申请人提供）：这项工作的总体目标是确定胃肠道肽，特别是胆囊收缩素（CCK）减少食物摄入的神经机制，并最终了解这些底物如何参与食物摄入和体重的生理和病理。CCK由肠粘膜细胞释放，响应肠内的营养物质。CCK也由大脑中离散的神经元群合成和分泌。最近的证据表明，除了控制单餐量，CCK也可能有助于控制长期食物摄入和体重增加。CCK控制长期食物摄入和体重增加的机制尚未得到研究。然而，最近的研究结果表明，CCK和脂肪细胞激素瘦素之间的协同作用促进了长期食物摄入和体重的控制。此外，我们实验室的初步结果表明，下丘脑的CCK受体在CCK对长期食物摄入和体重的控制中起着不可或缺的作用。在附件申请书中提出的实验将通过测试三个假设来研究CCK和CCK受体在长期食物摄入和体重控制中的作用。首先，我们将使用手术和肠道输注方法来验证外源性CCK和内源性CCK都通过作用于辣椒素敏感的传入神经元和CCK- a受体来增强脑瘦素对减肥和减少食物摄入的作用的假设。其次，通过肠道、动脉和静脉注射肽，我们将验证瘦素直接作用于迷走神经传入神经元和/或与CCK协同作用的假设，以减少短期食物摄入并增强瘦素对长期食物摄入的影响。最后，我们将开发一种新的靶向毒素，选择性地破坏表达CCK受体的特定脑神经元群，以验证CCK受体下丘脑神经元离散群参与控制长期每日食物摄入和体重增加的假设。这些实验旨在探索CCK受体在中枢和外周体重控制中的作用。这样的作用对于理解在健康和疾病中控制体重和食物摄入的机制具有开创性的重要性。

DESCRIPTION (provided by applicant): The overall goals of this work are to define the neural mechanisms through which gastrointestinal peptides, especially cholecystokinin (CCK), reduce food intake and ultimately to appreciate how these substrates are involved in the physiology and pathology of food intake and body weight. CCK is released by intestinal mucosal I cells, in response to nutrients in the intestine. CCK also is synthesized and secreted by discrete populations of neurons in the brain. Recent evidence suggests that in addition to controlling the size of individual meals, CCK may also contribute to the control of long-term food intake and body weight gain. The mechanisms by which CCK contributes to control of long-term food intake and body weight gain have not be investigated. However, recent findings suggest that control of long-term food intake and body weight is facilitated by synergistic interactions between CCK and the fat cell hormone, leptin. In addition, preliminary results from our laboratory indicate that CCK receptors in the hypothalamus play an integral role in the control of long-term food intake and body weight by CCK. The experiments proposed in the attached application will investigate the participation of CCK and CCK receptors in the control of long-term food intake and body weight by testing three hypotheses. First we will use surgical and intestinal infusion methodology to test the hypothesis that exogenous CCK and endogenous CCK both enhance the effect of brain leptin on weight loss and reduction of food intake by actions on capsaicin-sensitive afferent neurons and CCK-A receptors. Second, using intestinal, arterial and intravenous peptide infusions we will test the hypothesis that leptin acts directly on vagal afferent neurons alone and/or in concert with CCK to reduce short-term food intake and enhance leptin effects on long-term food intake. Finally, we will us a novel targeted toxin to selectively destroy specific populations of brain neurons that express CCK receptors, in order to test the hypothesis that discrete populations of CCK receptive hypothalamic neurons participate in control of long-term daily food intake and body weight gain. These experiments are intended to explore an expanded role for control of body weight by both central and peripheral CCK receptors. Such a role could well be of seminal importance to understanding the mechanism by which body weight and food intake are controlled in health and disease.