The Genetic Basis of Obesity and Neuronal Control of Energy Balance in Drosophila melanogaster
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.
- Identify pathways within the fat body that control organismal fat A significant fraction of the other genes from our screen displayed strong FB expression, including an endopeptidase with homologs that process neuropeptides, and a predicted
fatty-acid binding protein also detected in the hemolymph. Tissue-specific manipulation of such genes and molecular analysis of the defects in these mutants will identify those that, like Sir2, act autonomously in the FB to maintain proper
organismal fat levels.
- Determine the role in body fat regulation of a putative nutrient-responsive modifier of physical activity In our screen we identified a gene in neurosecretory cells of the brain that has been suggested to modify physical activity levels in
response to diet. We aim to describe a novel neuronal mechanism by which non-feeding physical activity regulates Drosophila body fat.
- Develop a functional map of neuronal control of body fat We identified 72 lines in which silencing of different regions of the larval brain increased body fat, and localized the affected neurons. The resulting map of neuronal fat regulation
represents the starting point for detailed dissection of signaling pathways between the brain and other tissues responsible for organismal energy homeostasis.