Regulation of long term feeding and triglyceride storage using Drosophila

利用果蝇调节长期饲养和甘油三酯储存

• 批准号: 7037874
• 负责人: Pankaj Kapahi
• 金额: $ 19.4万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037874
• 关键词: Drosophilidae; adenine nucleotides; appetite; arthropod genetics; behavioral /social science research tag; behavioral genetics; bioenergetics; body physical activity; dietary carbohydrates; dietary lipid; dietary proteins; disease /disorder model; fungal proteins; genetic strain; genetic susceptibility; glucose; lipid metabolism; nutrition related tag; obesity; overeating; respiratory oxygen; site directed mutagenesis; triglycerides

DESCRIPTION (provided by applicant): We propose to study the genetic basis of obesity using Drosophila. Obesity results from a greater energy intake than energy expenditure. Hence, the modification of eating behavior seems essential to avert the obesity crisis. We seek to identify dysregulation in metabolic feedback regulation leading to overeating in Drosophila. Excess nutrients are stored as triglycerides during obesity. We have observed that nutrient quality can modulate triglyceride storage in Drosophila. We propose to study the genetic basis for how nutrient quality can cause changes in triglyceride storage. Firstly, we propose to identify and characterize genes that regulate the long-term feeding rate of carbohydrates in Drosophila, which have been shown to possess such regulatory mechanisms. We have developed a rapid screening method, to identify strains that fail to inhibit feeding behavior after prolonged exposure to a diet containing excess carbohydrates. Using P element mediated mutagenesis we shall identify genes that regulate long term feeding behavior in Drosophila. From a pilot screen of 200 strains we have isolated two strains that fail to show a reduced inhibition of feeding rate in spite of being fed a diet rich in carbohydrates. The isolated mutants will be characterized for their energy status, mortality rate, physical activity, metabolic rate and respiratory quotient to give us better insight into the link between food intake and metabolism. Secondly, we aim to identify and characterize genes that regulate triglyceride storage. As part of our study, we shall examine dietary manipulations that recapitulate the "Atkins effect". A protein-rich, carbohydrate-poor diet, which is claimed to help lose fat in humans, also reduces fat in Drosophila. We aim to uncover the genetic basis for the reduction of fat on a diet that is rich in protein source using Drosophila. We propose to screen for regulators of triglyceride storage upon varying protein source (yeast extract) in the fly using P element mediated mutagenesis. Drosophila display long-term regulation of feeding behavior and obesity phenotypes like humans. The advanced genetic tools, the speed of discovery, and the complex nervous system of Drosophila make it an excellent choice as a model organism for examining causes of obesity. Given the high degree of genetic homology between humans and flies, we believe it is timely to examine the genetic causes of obesity in Drosophila. Our findings will significantly affect our understanding of the causes of obesity, which is a growing epidemic in the world.

描述（由申请人提供）： 我们建议利用果蝇研究肥胖的遗传基础。肥胖是由于能量摄入多于能量消耗造成的。因此，改变饮食行为对于避免肥胖危机似乎至关重要。我们试图找出导致果蝇暴饮暴食的代谢反馈调节失调。肥胖期间多余的营养物质会以甘油三酯的形式储存。我们观察到营养质量可以调节果蝇的甘油三酯储存。我们建议研究营养质量如何导致甘油三酯储存变化的遗传基础。 首先，我们建议鉴定和表征果蝇中调节碳水化合物长期摄食率的基因，这些基因已被证明具有这种调节机制。我们开发了一种快速筛选方法，以识别长期暴露于含有过量碳水化合物的饮食后无法抑制摄食行为的菌株。使用 P 元件介导的诱变，我们将鉴定调节果蝇长期摄食行为的基因。从 200 个菌株的初步筛选中，我们分离出两种菌株，尽管饲喂富含碳水化合物的饮食，但它们并未表现出对摄食率的抑制降低。分离出的突变体将根据其能量状态、死亡率、体力活动、代谢率和呼吸商进行表征，以便我们更好地了解食物摄入和新陈代谢之间的联系。 其次，我们的目标是识别和表征调节甘油三酯储存的基因。作为我们研究的一部分，我们将检查概括“阿特金斯效应”的饮食控制。富含蛋白质、缺乏碳水化合物的饮食据称有助于人类减脂，也能减少果蝇的脂肪。我们的目标是利用果蝇揭示富含蛋白质来源的饮食中减少脂肪的遗传基础。我们建议使用 P 元件介导的诱变来筛选果蝇中不同蛋白质来源（酵母提取物）的甘油三酯储存调节剂。 果蝇像人类一样表现出对摄食行为和肥胖表型的长期调节。果蝇先进的遗传工具、发现速度和复杂的神经系统使其成为研究肥胖原因的模式生物的绝佳选择。鉴于人类和果蝇之间的高度同源性，我们认为现在是时候检查果蝇肥胖的遗传原因了。我们的研究结果将极大地影响我们对肥胖原因的理解，肥胖在世界范围内日益流行。