Regulation of Food Intake and Body Weight by Amylin

胰淀素（也称为胰岛淀粉样蛋白多肽或IAPP）是一种由37个氨基酸组成的肽，在进食后与胰腺中的胰岛素共同产生和分泌。胰淀素也存在于肠内分泌细胞、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，胰淀素能有效地减少食物摄入、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和肥胖。靶向破坏胰淀素基因的小鼠在4个月大时体重增加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起着至关重要的作用。因此，我们有理由推测，胰淀素分泌不足或胰淀素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，因为血浆胰淀素的显著升高与胰腺癌患者早期严重的恶病质有关。研究旨在验证胰淀素作为一种激素信号向大脑传递，以减少食物摄入并调节脂肪能量储备的假设。大鼠和amylin- null突变小鼠模型将用于验证这一假设。具体目标是：1。确定胰淀粉酶是否作为一种必要的激素信号（通过血液）来减少食物摄入、体重和肥胖。2. 确定血浆胰淀素对摄入（或灌胃）不同营养物质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、体重和肥胖的来源和部位是否在外周和/或大脑。这些研究将促进我们对胰淀素在控制食物摄入和长期调节能量储备中的生理作用的理解。它们也可能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。

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.