Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila

PLoS Genet. 2015 May 21;11(5):e1005263. doi: 10.1371/journal.pgen.1005263. eCollection 2015 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Eating*
  • Fasting*
  • Gene Expression Regulation
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Homeostasis
  • Lipase / genetics
  • Lipase / metabolism
  • Lipolysis*
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction

Substances

  • Drosophila Proteins
  • Protein Kinases
  • salt-inducible kinase 3, Drosophila
  • LKB1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Lipase
  • BMM protein, Drosophila
  • HDAC4 protein, Drosophila
  • Histone Deacetylases

Grant support

This work was supported by the National Creative Research Initiatives grant funded by the Korea government (MSIP) (No. 2010-0018291). JC was supported by the BK Plus program provided by Korean Ministry of Education. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.