The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila

WANG, B., GOODE, J., BEST, J., MELTZER, J., SCHILMAN, P.E., CHEN, J. GARZA, D., THOMAS, J.B. & MONTMINY, M.

Cell Metabolism

Cell press, Elsevier

Año: 2008 vol. 7 p. 434 - 444

In fasted mammals, glucose homeostasis is maintained through activation of the cAMP responsive CREB coactivator TORC2, which stimulates the gluconeogenic program in concert with the forkhead transcription factor FOXO1 (Koo et al., 2005). Whether TORC2 and FOXO pathways act independently in response to fasting signals, however, remains unclear. Here we show that TORC is also activated during starvation in Drosophila, where it maintains energy balance by triggering the expression of CREB target genes that function in reactive oxygen species (ROS) scavenging. TORC mutant flies have reduced glycogen and lipid stores, and they are sensitive to starvation as well as oxidative stress. TORC was found to promote fasting metabolism independently of FOXO in the brain of adult flies; neuronal TORC expression rescued starvation and oxidative stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited fasting gene expression in wild type flies by stimulating the Salt Inducible Kinase 2 (SIK2)-mediated Ser157 phosphorylation and subsequent degradation of TORC. Indeed, RNAi mediated knockdown of Drosophila SIK2 reduced amounts of Ser157 phosphorylated TORC and enhanced starvation resistance in adult flies. As disruption of insulin signaling, either by ablation of insulin-producing cells (IPCs) (Broughton et al., 2005) or by mutation of the insulin receptor adaptor gene chico, increased TORC activity during refeeding, our results illustrate a second insulin-regulated pathway that functions in parallel with FOXO to promote energy balance in Drosophila.