Regulation of Food Intake and Body Weight by Amylin

胰淀素对食物摄入量和体重的调节

• 批准号: 6796116
• 负责人: ROGER REIDELBERGER
• 金额: $ 2.15万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796116
• 关键词: amylin; anorexia; bioenergetics; biological signal transduction; body weight; cachexia; cholecystokinin; hormone receptor; hormone regulation /control mechanism; hypothalamus; insulin; laboratory mouse; laboratory rat; leptin; malnutrition; neurons; neuroregulation; nutrient intake activity; nutrition related tag; obesity; pancreas neoplasms; pathologic process; peptide hormone biosynthesis; satiations

Amylin (also called Islet Amyloid Polypeptide or IAPP) is a 37 amino acid peptide that is co-produced and secreted with insulin from the pancreas in response to a meal. Amylin is also found in gut endocrine cells, visceral sensory neurons, and hypothalamus. When administered systemically or into the brain of rats amylin potently reduces food intake, body weight and/or adiposity. In contrast, amylin receptor blockade using AC187 has been reported to increase food intake and adiposity. Mice with targeted destruction of the amylin gene develop a 29 percent larger body weight at 4 months of age. Together, these results suggest that amylin plays an essential role in control of food intake and long-term regulation of energy reserves. Thus, it is reasonable to speculate that insufficient amylin production or amylin-insensitivity may contribute to the development of obesity. Amylin may also play a pathophysiological role in the malnutrition associated with pancreatic cancer, because marked elevation of plasma amylin occurs in association with the early, severe cachexia in pancreatic cancer patients. Studies are designed to test the hypothesis that pancreatic amylin acts as a hormonal signal to the brain to reduce food intake and to regulate adipose energy reserves. Rat and amylin- null mutant mouse models will be used to test this hypothesis. Specific aims are to: 1. Determine whether amylin acts as an essential hormonal signal (via the bloodstream) to decrease food intake, body weight, and adiposity. 2. Determine whether plasma amylin responses to ingestion (or intragastric infusion) of different nutrients are sufficient to decrease food intake and body weight. 3. Determine whether amylin reduces food intake, body weight, and adiposity through a synergistic interaction with CCK and leptin, peptides known to contribute to the production of satiety and the long-term regulation of energy reserves. 4. Determine whether the source and site of endogenous amylin action to reduce food intake, body weight, and adiposity is in the periphery and/or brain. These studies should advance our understanding of the physiological role of amylin in control of food intake and the long-term regulation of energy reserves. They may also provide direction in the search for pathogenic mechanisms of eating and metabolic disorders and strategies for their treatment.

胰淀素（也称为胰岛淀粉样多肽或 IAPP）是一种由 37 个氨基酸组成的肽，在进食时与胰腺中的胰岛素共同产生和分泌。 胰淀素也存在于肠道内分泌细胞、内脏感觉神经元和下丘脑中。 当全身给药或进入大鼠大脑时，胰淀素可有效减少食物摄入、体重和/或肥胖。 相比之下，据报道使用 AC187 阻断胰淀素受体会增加食物摄入量和肥胖。 胰淀素基因被靶向破坏的小鼠在 4 个月大时体重增加了 29%。 总之，这些结果表明胰淀素在控制食物摄入和长期调节能量储备方面发挥着重要作用。 因此，有理由推测胰岛淀粉样多肽产生不足或胰岛淀粉样多肽不敏感可能导致肥胖的发生。 胰淀素也可能在与胰腺癌相关的营养不良中发挥病理生理作用，因为血浆胰淀素显着升高与胰腺癌患者的早期、严重恶病质有关。研究旨在检验胰岛淀粉样蛋白作为大脑的激素信号以减少食物摄入和调节脂肪能量储备的假设。 大鼠和胰岛淀粉样蛋白缺失突变小鼠模型将用于检验这一假设。具体目标是： 1. 确定胰淀素是否作为一种重要的激素信号（通过血液）发挥作用，以减少食物摄入、体重和肥胖。 2. 确定血浆胰淀素对不同营养素的摄入（或胃内输注）的反应是否足以减少食物摄入和体重。 3. 确定胰淀素是否通过与 CCK 和瘦素（已知有助于产生饱腹感和长期调节能量储备的肽）的协同相互作用来减少食物摄入、体重和肥胖。 4.确定内源性胰淀素减少食物摄入、体重和肥胖的作用的来源和部位是否在外周和/或大脑中。这些研究应该增进我们对胰淀素在控制食物摄入和长期调节能量储备方面的生理作用的理解。 它们还可以为寻找饮食和代谢紊乱的致病机制及其治疗策略提供方向。