Regulation of long term feeding and triglyceride storage using Drosophila

Buck Institute For Research On Aging, Novato CA

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Abstract

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.