The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila.
In fasted mammals, glucose homeostasis is maintained through induction of the cAMP response element-binding protein (CREB) coactivator transducer of regulated CREB activity 2 (TORC2), which stimulates the gluconeogenic program in concert with the forkhead factor FOXO1. Here we show that starvation also triggers TORC activation in Drosophila, where it maintains energy balance through induction of CREB target genes in the brain. TORC mutant flies have reduced glycogen and lipid stores and are sensitive to starvation and oxidative stress. Neuronal TORC expression rescued stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited TORC activity through the salt-inducible kinase 2 (SIK2)-mediated phosphorylation and subsequent degradation of TORC. Depletion of neuronal SIK2 increased TORC activity and enhanced stress resistance. As disruption of insulin signaling also augmented TORC activity in adult flies, our results illustrate the importance of an insulin-regulated pathway that functions in the brain to maintain energy balance.
Wang
Biao
B
Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA 92037, USA.
Goode
Jason
J
Best
Jennifer
J
Meltzer
Jodi
J
Schilman
Pablo E
PE
Chen
Jian
J
Garza
Dan
D
Thomas
John B
JB
Montminy
Marc
M
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008055:Lipids; D008297:Male; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013217:Starvation; D014157:Transcription Factors / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D010446:Peptide Fragments; D014157:Transcription Factors; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases