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64%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。现在很清楚，肥胖主要是由于遗传倾向，成为超重加上行为变化和环境因素，促进增加热量摄入和久坐不动的生活方式。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）是由沿着从胃到直肠的肠道的内分泌细胞、胰腺α细胞和孤束核、邻近背内侧髓网状结构和嗅球中的离散脑神经元群产生的一种氨基酸肽。在啮齿类动物中，全身或脑内给予GLP-1可有效降低摄食量和体重，脑内给予GLP-1受体拮抗剂exendin（9-39）可增加摄食量和体重。肥胖的人似乎对食物摄入具有钝化的血浆GLP-1响应;然而低剂量的GLP-1在瘦和肥胖的人中类似地减少食物摄入。这些结果表明，GLP-1可能在生理上起到减少食物摄入和身体肥胖的作用，并且GLP-1的产生不足可能促进肥胖。食物摄入会释放至少两种形式的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检验以下假设：由肠道响应于进餐而分泌的GLP-1形式充当大脑产生饱腹感和减少肥胖的信号，并且这些信号的产生和/或作用不足有助于肥胖的产生。具体目的是：i）确定当静脉内输注时，GLP-1是否是用于减少食物摄入的最有效和最有效的GLP-1形式。2)确定产酶GLP-1形式是否与其他假定的饱腹感和肥胖调节因子[胆囊收缩素、胰淀素、胃泌酸调节素、肽YY（3-36）、瘦素]协同作用以减少摄食量。3)使用新型蛋白质组学方法、GLP-1形式拮抗剂（受体拮抗剂、免疫中和抗血清）和腹部迷走神经去神经支配，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传导来减少摄食量。4)确定在饮食诱导的肥胖大鼠中，产脂性GLP-1形式的产生和/或作用是否减少。5)确定特定模式的促氧化GLP-1形式长期给药（单独或与其他假定的饱腹感和肥胖调节因子联合给药）是否可使饮食诱导的肥胖大鼠每日摄食量和肥胖持续减少。