Regulation of Food Intake and Body Weight by GLP-1

GLP-1 对食物摄入量和体重的调节

• 批准号: 7144466
• 负责人: ROGER REIDELBERGER
• 金额: $ 24.02万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144466
• 关键词: amylin; anorexic agent; appetite; body weight; cholecystokinin; denervation; drug interactions; gastrointestinal hormones; hormone regulation /control mechanism; incretin hormone; injection /infusion; laboratory rat; leptin; neuropharmacology; neuroregulation; nutrient intake activity; obesity; proteomics; satiations

DESCRIPTION (provided by applicant): More than 64% of US adults are overweight, with nearly 31% (over 61 million) meeting criteria for obesity. There is a clear link between obesity and development of diabetes, heart disease, many cancers, and depression. It is now clear that obesity primarily results from a genetic predisposition to become overweight coupled with behavioral changes and environmental factors that promote increased caloric intake and sedentary lifestyles. Thus, defining the physiological mechanisms that control food intake provides direction in the search for pathogenic mechanisms of obesity and strategies for prevention and treatment of obesity-related diseases. Glucagon-like peptide-1(7-36)-amide (called GLP-1) is a so-amino acid peptide produced by endocrine cells along the gut from stomach to rectum, pancreatic alpha-cells, and discrete populations of brain neurons in the nucleus of the solitary tract, adjacent dorsomedial medullary reticular formation, and olfactory bulb. In rodents, GLP-1 potently reduces food intake and body weight when given systemically or into the brain, and administration of the GLP-1 receptor antagonist exendin(9-39) into the brain increases food intake and body weight. Obese humans appear to have a blunted plasma GLP-1 response to food intake; yet low doses of GLP-1 decrease food intake similarly in lean and obese humans. These results suggest that GLP-1 may act physiologically to reduce food intake and body adiposity, and that insufficient production of GLP-1 may promote obesity. Food intake releases at least two forms of GLP-1 into the circulation: GLP-1 and GLP-1(7-36)-Gly; other predicted/detected GLP-1 forms in gut tissue and blood include GLP-1(7-36)-Gly- Arg-Arg, GLP-1(1-36)-amide, GLP-1(1-36)-Gly, and GLP-1(1-36)-Gly-Arg-Arg. Studies will use established rat models to test the hypotheses that GLP-1 form(s) secreted by the gut in response to a meal act as signal(s) to the brain to produce satiety and reduce adiposity, and that insufficient production and/or action of these signal(s) contribute to the production of obesity. Specific aims are to: i) Determine whether GLP-1, when infused intravenously, is the most potent and efficacious GLP-1 form for reducing food intake. 2) Determine whether anorexigenic GLP-1 form(s) act synergistically with other putative satiety and adiposity regulatory factors [cholecystokinin, amylin, oxyntomodulin, peptide YY(3-36), leptin] to reduce food intake. 3) Use novel proteomic methods, antagonists of GLP-1 forms (receptor antagonist, immunoneutralizing antiserum), and abdominal vagal denervation to determine whether GLP-1 form(s) act through endocrine and/or paracrine control of vagal signaling from gut to brain to reduce food intake. 4) Determine whether production and/or action of anorexigenic GLP-1 form(s) are reduced in diet-induced obese rats. 5) Determine whether specific patterns of chronic administration of anorexigenic GLP-1 form(s), alone or in combination with the other putative satiety and adiposity regulatory factors, can produce a sustained reduction in daily food intake and adiposity in diet-induced obese rats.

描述（由申请人提供）：超过64％的美国成年人超重，近31％（超过6100万）满足肥胖标准。肥胖与糖尿病，心脏病，许多癌症和抑郁症之间存在明确的联系。现在很明显，肥胖主要是由于遗传倾向而产生的，它会超重，再加上行为变化和环境因素，从而促进了卡路里的摄入量增加和久坐的生活方式。因此，定义控制食物摄入的生理机制为寻找肥胖症的致病机制和预防和治疗肥胖相关疾病的策略提供了方向。胰高血糖素肽-1（7-36） - 酰胺（称为GLP-1）是一种由内分泌细胞从肠道到直肠到直肠的肠道，胰腺α细胞，胰腺α细胞，脑神经元的离散型脑神经元群体中产生的So-氨基酸肽。在啮齿动物中，GLP-1在全身或进入大脑时有效减少食物的摄入量和体重，而GLP-1受体拮抗剂外脱素（9-39）的给药会增加食物的摄入量和体重。肥胖的人类似乎对食物摄入的血浆GLP-1反应钝。然而，低剂量的GLP-1在瘦和肥胖的人类中类似地降低了食物摄入量。这些结果表明，GLP-1可以在生理上起作用以减少食物摄入和身体肥胖，而GLP-1的产生不足可能会促进肥胖症。食物摄入量至少将两种形式的GLP-1释放到循环中：GLP-1和GLP-1（7-36） - 格莱；肠道组织和血液中的其他预测/检测到的GLP-1形式包括GLP-1（7-36）-Gly-Arg-Arg，GLP-1（1-36）-Amide，GLP-1（1-36） - glp-1（1-36） - glp-1（1-36）（1-36）-gly-arg-arg-arg。研究将使用已建立的大鼠模型来检验肠道分泌的GLP-1形成的假设，该假设是响应餐食的响应，作为大脑的信号，以产生饱腹感和减少肥胖，并且这些信号的产生和/或作用不足有助于产生肥胖。具体目的是：i）确定GLP-1在静脉注射时是否是减少食物摄入量的最有效和有效的GLP-1形式。 2）确定厌食症GLP-1形式是否与其他推定的饱腹感和肥胖调节因子协同作用[胆囊基蛋白，淀粉蛋白，氧基诺抑制蛋白，肽YY（3-36），瘦素，瘦素，以减少食物摄入量。 3）使用新型的蛋白质组学方法，GLP-1形式的拮抗剂（受体拮抗剂，免疫中和抗血清）和腹部迷走神经神经膜来确定GLP-1的形式是否通过内分泌和/或旁花对肠道的迷走神经控制来起作用，以减少脑的肠道信号，以减少食物的摄入量。 4）确定饮食诱导的肥胖大鼠的厌食性GLP-1形式的产生和/或作用是否降低。 5）确定单独或与其他推定的饱腹感和肥胖调节因素结合的慢性厌食性GLP-1形式的特定模式是否可以持续降低饮食诱发的肥胖大鼠的日常食物摄入和肥胖。