title: Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila.
abstract: LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea; National Creative Research Initiatives Center for Energy Homeostasis Regulation, Seoul National University, Seoul, Republic of Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sekyu
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea; National Creative Research Initiatives Center for Cell Division and Differentiation, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: National Creative Research Initiatives Center for Energy Homeostasis Regulation, Seoul National University, Seoul, Republic of Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004435:Eating; D005215:Fasting; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D011494:Protein Kinases; C559671:salt-inducible kinase 3, Drosophila; C495775:LKB1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D008049:Lipase; C559670:BMM protein, Drosophila; C559672:HDAC4 protein, Drosophila; D006655:Histone Deacetylases