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(申请人提供)：超过%的美国成年人超重，近31%(超过6100万)符合肥胖标准。肥胖与糖尿病、心脏病、许多癌症和抑郁症的发展之间存在明显的联系。现在很明显，肥胖主要是由超重的遗传倾向以及行为变化和环境因素造成的，这些因素促进了卡路里摄入量的增加和久坐不动的生活方式。因此，明确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(又称GLP-1)是一种由胃到直肠的内分泌细胞、胰腺α细胞以及孤束核、邻近的背内侧延髓网状结构和嗅球的离散脑神经元群产生的一种氨基酸多肽。在啮齿类动物中，GLP-1有效地减少了食物的摄入量和体重，当系统地或进入大脑时，GLP-1受体拮抗剂exendin(9-39)进入大脑增加食物的摄入量和体重。肥胖的人似乎对食物摄入的血浆GLP-1反应迟钝；然而，低剂量的GLP-1减少了瘦人和肥胖者的食物摄入量。这些结果表明，GLP-1可能在生理上起到减少食物摄入量和身体肥胖的作用，而GLP-1的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；其他在肠道组织和血液中预测/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检验这样的假设，即肠道对进食的反应产生的GLP-1形式(S)作为信号(S)向大脑发出信号，产生饱腹感和减少肥胖，以及这些信号的产生和/或作用不足(S)导致肥胖的产生。具体目的是：i)确定静脉输注GLP-1是否是减少食物摄入的最有效的GLP-1形式。2)确定厌食性糖蛋白-1形式(S)是否与其他可能的饱腹感和肥胖调节因子[胆囊收缩素、胰淀素、氧合酶调节蛋白、多肽YY(3-36)、瘦素]协同作用，减少摄食量。3)使用新的蛋白质组学方法、GLP-1形式的拮抗剂(受体拮抗剂、免疫中和抗血清)和腹部迷走神经失神经来确定GLP-1形式(S)是否通过内分泌和/或旁分泌控制迷走神经从肠道到大脑的信号来减少摄食量。4)确定食源性肥胖大鼠厌食性GLP-1(S)的产生和/或作用是否减少。5)确定长期给予特定形式的厌食性GLP-1(S)，单独或与其他可能的饱腹感和肥胖调节因子联合使用，是否可以持续减少饮食诱导的肥胖大鼠的每日摄食量和肥胖。