title: A hormone-dependent module regulating energy balance.
abstract: Under fasting conditions, metazoans maintain energy balance by shifting from glucose to fat burning. In the fasted state, SIRT1 promotes catabolic gene expression by deacetylating the forkhead factor FOXO in response to stress and nutrient deprivation. The mechanisms by which hormonal signals regulate FOXO deacetylation remain unclear, however. We identified a hormone-dependent module, consisting of the Ser/Thr kinase SIK3 and the class IIa deacetylase HDAC4, which regulates FOXO activity in Drosophila. During feeding, HDAC4 is phosphorylated and sequestered in the cytoplasm by SIK3, whose activity is upregulated in response to insulin. SIK3 is inactivated during fasting, leading to the dephosphorylation and nuclear translocation of HDAC4 and to FOXO deacetylation. SIK3 mutant flies are starvation sensitive, reflecting FOXO-dependent increases in lipolysis that deplete triglyceride stores; reducing HDAC4 expression restored lipid accumulation. Our results reveal a hormone-regulated pathway that functions in parallel with the nutrient-sensing SIRT1 pathway to maintain energy balance.
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Wang
authors.forename: Noel
authors.initials: N
authors.lastname: Moya
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Heather
authors.initials: H
authors.lastname: Hoover
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mihaylova
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Fischer
authors.forename: John B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D004435:Eating; D004734:Energy Metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D014280:Triglycerides; C559671:salt-inducible kinase 3, Drosophila; D017346:Protein Serine-Threonine Kinases; D008049:Lipase; C559670:BMM protein, Drosophila; C559672:HDAC4 protein, Drosophila; D006655:Histone Deacetylases