GASTROINTESTINAL SITES REGULATE REDUCTION OF BODY WEIGHT BY GASTRIN-RELEASING PEPTIDE

项目概要（项目1） 治疗肥胖需要了解调节短期控制食物的机制 摄入量，即，减少个人膳食量（MS）的因素;延长连续两餐之间的时间， 称为餐间间隔（IMI）;并导致体重减轻。拟议的努力将涉及 评价短期饱腹肽，胃泌素释放肽（GRP）的抗肥胖作用， 测试假设，如果在饮食诱导的肥胖大鼠中，GRP以低量注射， 高度特异性的胃肠道部位，它有效和安全地减少MS和延长IMI (i.e.,增加饱腹感），导致体重减轻。有三个具体目标：具体 目的I：确定控制MS、IMI长度和体重（BW）的特定胃肠道作用部位 由正常饮食释放的内源性GRP引起。特定目的II：确定特定胃肠道部位 外源性GRP-10（GRP的羧基末端十肽）控制MS、IMI长度和BW的作用 和GRP-29（GRP的大分子形式）。具体目标III：确定特定胃肠道部位 通过蛋白胨释放的内源性GRP控制MS、IMI长度和BW。此外， 肽和拮抗剂的输注将通过检查细胞的形态和重量来评价。 单次和长期输注GRP后的特定肠道作用部位。我们将测试这三个目标， 创新的方法，包括使用（a）主要动脉的微血管导管插入术及其 （B）一种灵敏的酶免疫测定法，其测定GRP的水平， （c）Fos样免疫反应性的免疫组织化学检测，Fos样免疫反应性是神经元激活的标志物， 肠神经元和背迷走神经复合体;（d）饮食诱导的肥胖大鼠;和（e）自动BioDAQ 给料装置这项工作将建立，在饮食诱导的肥胖大鼠，具体的作用部位调节 通过内源性和外源性GRP测定膳食量、IMI和BW，并将确定GRP是否可在 人类作为抗肥胖药物。

PROJECT SUMMARY (Project 1) Treatment of obesity requires an understanding of the mechanisms that regulate the short-term control of food intake, i.e., factors that reduce individual meal size (MS); prolong the time between two consecutive meals, known as the inter-meal interval (IMI); and result in reduction of body weight. The proposed effort will involve evaluation of the anti-obesity effects of the short-term satiety peptide, gastrin-releasing peptide (GRP) by testing the hypothesis that, if, in diet-induced obese rats, GRP is injected in low amounts and at highly specific gastrointestinal sites, it effectively and safely reduces MS and extends the IMI (i.e., increases satiety), resulting in reduction in body weight. There are three Specific Aims: Specific Aim I: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and body weight (BW) by endogenous GRP released by a normal meal. Specific Aim II: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and BW by exogenous GRP-10 (a COOH-terminal decapeptide of GRP) and GRP-29 (a large molecular form of GRP). Specific Aim III: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and BW by endogenous GRP released by peptone. In addition, the safety of infusions of the peptides and antagonists will be evaluated by examining the morphology and weights of the specific gut sites of action following single and chronic infusions of GRP. We will test these three aims by innovative approaches, including use of (a) microvascular catheterization of the major arteries and their branches in the gut, (b) a sensitive enzyme immunoassay that determines the levels of GRP in response to meals; (c) immunohistochemical detection of Fos-like immunoreactivity, a marker for neuronal activation in the enteric neurons and in the dorsal vagal complex; (d) diet-induced obese rats; and (e) the automated BioDAQ feeding apparatus. This work will establish, in diet-induced obese rats, the specific site(s) of action regulating meal size, IMI, and BW by endogenous and exogenous GRP and will determine if GRP can be tested in humans as an anti-obesity medication.