Genetic background is a strong predisposing factor for obesity, but we currently understand only a few affected pathways. Our overall goal is to find new hereditary risk factors for obesity and determine how they work. Our research focuses on addressing the following questions: What pathways within fat storage tissues control the balance between energy storage and mobilization? How are feeding and physical activity coordinated to prevent excess stored fat? How do tissues communicate energy demands to the brain? We developed the fly larvae as a powerful model to investigate how an organism balances energy expenditure and storage. Despite its conserved and complex physiology, in Drosophila a single gene usually performs the function of a family of related mammalian genes, and can be manipulated experimentally in specific tissues, crucial advantages for the analysis of gene function.
We devised a novel genetic screen using a buoyancy-based assay for body fat (Figure), and employed gas chromatography/ mass spectrometry (GC/MS) to confirmed that floating larvae have more stored lipids. We identified 66 genes, representing the first unbiased genetic screen for fat mutant larvae.
We showed that one of these genes, Sir2, regulates organismal fat levels in the fat body (FB), the fly fat storage tissue. Sir2 mutants accumulate energy stores without feeding more. Conversely, FB-specific Sir2 overexpression depletes energy stores. Sir2 is thus necessary and sufficient for a nutrient-sensitive switch to catabolism of stored energy, providing an organismal context for the coordination of sirtuin function in different tissues to achieve energy balance.