Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways

J Biol Chem. 2009 Aug 14;284(33):22426-35. doi: 10.1074/jbc.M109.028357. Epub 2009 Jun 11.


The binding of the adaptor protein APPL1 to adiponectin receptors is necessary for adiponectin-induced AMP-activated protein kinase (AMPK) activation in muscle, yet the underlying molecular mechanism remains unknown. Here we show that in muscle cells adiponectin and metformin induce AMPK activation by promoting APPL1-dependent LKB1 cytosolic translocation. APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol. Adiponectin also activates another AMPK upstream kinase Ca2+/calmodulin-dependent protein kinase kinase by activating phospholipase C and subsequently inducing Ca2+ release from the endoplasmic reticulum, which plays a minor role in AMPK activation. Our results show that in muscle cells adiponectin is able to activate AMPK via two distinct mechanisms as follows: a major pathway (the APPL1/LKB1-dependent pathway) that promotes the cytosolic localization of LKB1 and a minor pathway (the phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathway) that stimulates Ca2+ release from intracellular stores.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adiponectin / metabolism*
  • Animals
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism*
  • Carrier Proteins / metabolism*
  • Humans
  • Mice
  • Microscopy, Confocal / methods
  • Models, Biological
  • Muscles / enzymology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Subcellular Fractions / metabolism


  • APPL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Adiponectin
  • Appl1 protein, mouse
  • Carrier Proteins
  • STK11 protein, human
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • AMP-Activated Protein Kinases
  • Calcium