? Obesity is quickly becoming a major health issue in our society. This imbalance between energy input and output is in part mediated by inappropriate responses to hunger and satiation. We propose to develop an obesity model using the Drosophila larva that will enable us to rapidly identify, characterize and study interactions of dozens of genes that affect food related behaviors. This will provide us with candidate genes, mechanisms and pathways relevant to human obesity. These discoveries are vital to the development of new genetic and pharmaceutical therapies as well as preventative measures. ? Aim 1: Genes involved in the regulation of hunger and satiation: The normal behavioral response of a larva to an acute period of food deprivation is to increase its food intake and reduce its locomotor activity. A well-fed larva exhibits the opposite responses. We will perform an insertional mutagenesis screen to identify larvae with aberrant responses to these conditions. The range of effects of each mutation will be quantified. We will specifically measure the larva's food intake and activity levels in response to a series of food deprivation conditions, its health (growth rates, developmental times, survivorship), taste and olfactory abilities, and lipid levels. Evolutionary conservation of DNA sequences and gene function suggests that a subset of these newly discovered genes will play important roles in hunger and satiation signals in humans. ? Aim 2: Existing variants: Mutations in eight genes and one natural variant that cause well-fed larvae to alter food-related locomotor activities will be localized and characterized. ? Aim 3: Pathways involved in food-related behaviors: Gene interaction pathways of potential importance to human obesity will be determined by combining mutations and determining if the presence of a second mutation enhances or suppresses the phenotype of the first. ? Aim 4: Analysis of natural variation in food-related behaviors: Fly genes with human orthologs will be examined at the DNA level for functional polymorphisms associated with obesity-related phenotypes. ? This will suggest gene regions where functional human polymorphisms may reside. This is a first step in finding genetic variants that underlie human vulnerabilities to obesity ? ?
