Regulation of Food Intake and Body Weight by GLP-1

描述（由申请人提供）：超过64%的美国成年人超重，其中近31%（超过6100万）符合肥胖标准。肥胖与糖尿病、心脏病、许多癌症和抑郁症之间有着明显的联系。现在很清楚，肥胖主要是由于遗传因素导致的超重，再加上行为改变和环境因素导致的热量摄入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（GLP-1）是一种由沿肠道从胃到直肠的内分泌细胞、胰腺α细胞、孤立束核内离散的脑神经细胞群、邻近的背内侧髓网状结构和嗅球产生的氨基酸肽。在啮齿类动物中，GLP-1在全身或大脑中有效地减少食物摄入量和体重，而GLP-1受体拮抗剂exendin（9-39）进入大脑会增加食物摄入量和体重。肥胖的人似乎对食物摄入有迟钝的血浆GLP-1反应；然而，低剂量的GLP-1减少了瘦人和肥胖人的食物摄入量。这些结果表明，GLP-1可能在生理上起到减少食物摄入和身体肥胖的作用，而GLP-1分泌不足可能会促进肥胖。食物摄入释放至少两种形式的GLP-1进入循环：GLP-1和GLP-1(7-36)-Gly；其他预测/检测到的GLP-1在肠道组织和血液中的形式包括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验证以下假设：肠道在进食后分泌的GLP-1形式作为向大脑发出产生饱腹感和减少肥胖的信号，而这些信号的产生和/或作用不足会导致肥胖的产生。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)确定无氧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、氧合调节素、肽YY（3-36）、瘦素]协同作用以减少食物摄入。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）和腹部迷走神经去神经来确定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来减少食物摄入。4)确定饮食诱导的肥胖大鼠厌氧性GLP-1形式的产生和/或作用是否减少。5)确定慢性给药厌氧性GLP-1形式的特定模式，单独或与其他假定的饱腹感和肥胖调节因子联合，是否可以在饮食诱导的肥胖大鼠中产生持续的每日食物摄入量和肥胖的减少。

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.