In mammals, there appears to be an intimate linkage between insulin signaling, life span, and fat storage. Reductions in insulin signaling promote excess fat storage, and obesity can result in insulin insensitivity. We use the nematode C. elegans to address our hypothesis that multiple conserved signaling pathways including TGF-2 and TOR, modulate insulin/IGF-1 signaling to coordinately regulate life span and fat storage. C. elegans possess an insulin/IGF-1 signaling pathway that is well conserved across species. Modulating this pathway leads to changes in life span and fat storage. Therefore, worms are an excellent system to determine how multiple pathways influence the insulin/IGF-1 signaling pathway for life span and fat storage regulation. To address our hypothesis we will perform the following three specific aims (1) We will dissect the cross talk between the TGF-2 and insulin/IGF-1 pathways (2) We will dissect the cross talk the TOR and insulin/IGF-1 signaling (3) We will identify phosphatases that regulate the Insulin/IGF-1 signaling pathway to modulate life span and fat storage. These phosphatases may regulate the insulin/IGF-1 signaling pathway or one of the multiple conserved pathways that couple the insulin/IGF-1 pathway. Over the long term, these studies should help to understand the complexities associated with diseases such as Type II diabetes.
The insulin/IGF-1 signaling pathway is conserved across phylogeny. In this proposal, we dissect how additional conserved signaling pathways couple with the insulin/IGF-1 signaling pathway to cooperatively regulate life span and fat storage.
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