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% 的美国成年人体重超重，其中近 31%（超过 6100 万人）符合肥胖标准。肥胖与糖尿病、心脏病、多种癌症和抑郁症的发生之间存在明显的联系。现在已经清楚，肥胖主要是由于超重的遗传倾向，加上促进热量摄入增加和久坐生活方式的行为改变和环境因素造成的。因此，定义控制食物摄入的生理机制为寻找肥胖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。胰高血糖素样肽-1(7-36)-酰胺（称为 GLP-1）是一种氨基酸肽，由从胃到直肠的肠道内分泌细胞、胰腺 α 细胞和离散的大脑神经元群产生。孤束核、邻近的背内侧髓质网状结构和嗅球。在啮齿动物中，GLP-1 在全身给药或进入大脑时可有效减少食物摄入量和体重，而将 GLP-1 受体拮抗剂 exendin(9-39) 注射到大脑中会增加食物摄入量和体重。肥胖的人似乎对食物摄入的血浆 GLP-1 反应减弱；然而，低剂量的 GLP-1 会减少瘦人和肥胖人的食物摄入量。这些结果表明，GLP-1 可能在生理上发挥作用，以减少食物摄入和身体肥胖，并且 GLP-1 产生不足可能会促进肥胖。食物摄入至少释放两种形式的 GLP-1 进入循环：GLP-1 和 GLP-1(7-36)-Gly；肠道组织和血液中其他预测/检测到的 GLP-1 形式包括 GLP-1(7-36)-Gly-Arg-Arg、GLP-1(1-36)-酰胺、GLP-1(1-36)-Gly和GLP-1(1-36)-Gly-Arg-Arg。研究将使用已建立的大鼠模型来测试以下假设：肠道响应进餐而分泌的 GLP-1 形式作为向大脑发出的信号以产生饱腹感并减少肥胖，以及生产不足和/或这些信号的作用导致肥胖的产生。具体目标是： i) 确定静脉注射时 GLP-1 是否是减少食物摄入最有效的 GLP-1 形式。 2) 确定抑制食欲的 GLP-1 形式是否与其他推定的饱腹感和肥胖调节因子 [胆囊收缩素、胰淀素、泌酸调节素、肽 YY(3-36)、瘦素] 协同作用以减少食物摄入。 3) 使用新型蛋白质组学方法、GLP-1形式的拮抗剂（受体拮抗剂、免疫中和抗血清）和腹部迷走神经去神经术来确定GLP-1形式是否通过内分泌和/或旁分泌控制从肠道到大脑的迷走神经信号发挥作用以减少食物摄入量。 4)确定饮食诱导的肥胖大鼠中致食欲GLP-1形式的产生和/或作用是否减少。 5) 确定单独或与其他推定的饱腹感和肥胖调节因子组合长期施用致食欲 GLP-1 形式的特定模式是否可以使饮食诱导的肥胖大鼠的每日食物摄入量和肥胖持续减少。