he 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
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.