We use genetic approaches in Drosophila melanogaster to find new modifiers of the insulin signaling pathway. Drosophila is a top-notch model system for the study of insulin signaling for many reasons.  1) The entire insulin signal transduction pathway is highly conserved in the fly.  2) Mutations in genes involved in insulin signaling lead to robust and easily-screenable phenotypes: loss-of-function mutations generate small flies while gain-of-function mutations generate big flies. 3) The genetic approaches used in Drosophila research enable quick and easy cell- and tissue-specific studies of gene function.  4) Finally, nearly 75% of disease genes in humans have counterparts in the fly.

 

 

In obesity, signals from adipose-tissue macrophages with active Toll-like receptor signaling lead to impaired insulin signaling in adipocytes.  Insulin resistance in fat leads to insulin resistance in other tissues such as muscle and liver.  These interactions are conserved in the fruit fly: activation of the innate immune system via the Toll signaling pathway leads to impaired insulin signaling, reduced fat body growth and nutrient storage, and decreased growth of the whole animal.

 

 

 

 

Three major efforts in the lab are directed toward furthering our understanding of how the insulin signaling pathway responds to inputs from the Toll pathway and how both of these pathways control growth and nutrient metabolism:

 

 

1. We are working to identify genes that link activation of the innate immune system with insulin resistance.  To do so, we are conducting an unbiased, large-scale, forward genetic screen to find genes that rescue insulin-signaling defects in the context of active Toll signaling.  Our efforts are focused on genes that have clear human homologues, and we will work to translate our findings from to mammals.

 

 

2. We are directly investigating the mechanism of Toll-signaling dependent inhibition of phosphorylation of the insulin signaling kinase Akt using both biochemical and targeted forward genetic approaches.

 

 

3. We are investigating the regulation of nutrient metabolism by upstream signaling pathways in different contexts by coupling the power of mosaic analysis with new tools such as fluorescently-labeled metabolic tracers.