PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis

EMBO J. 2010 Jan 20;29(2):469-81. doi: 10.1038/emboj.2009.339. Epub 2009 Nov 26.


The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone-sensitive lipase (HSL). TAG resynthesis is associated with high-energy consumption, which when inordinate, leads to increased AMPK activity that acts to restrain hydrolysis of TAGs by inhibiting PKA-mediated activation of HSL. Here, we report that in primary mouse adipocytes, PKA associates with and phosphorylates AMPKalpha1 at Ser-173 to impede threonine (Thr-172) phosphorylation and thus activation of AMPKalpha1 by LKB1 in response to lipolytic signals. Activation of AMPKalpha1 by LKB1 is also blocked by PKA-mediated phosphorylation of AMPKalpha1 in vitro. Functional analysis of an AMPKalpha1 species carrying a non-phosphorylatable mutation at Ser-173 revealed a critical function of this phosphorylation for efficient release of free fatty acids and glycerol in response to PKA-activating signals. These results suggest a new mechanism of negative regulation of AMPK activity by PKA that is important for converting a lipolytic signal into an effective lipolytic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adipocytes / enzymology*
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Fatty Acids / metabolism
  • Glycerol / metabolism
  • Isoproterenol / pharmacology
  • Lipolysis*
  • Mice
  • Phosphorylation
  • Point Mutation
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Protein-Serine-Threonine Kinases / metabolism


  • Adrenergic beta-Agonists
  • Fatty Acids
  • Protein Subunits
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • AMP-Activated Protein Kinases
  • Isoproterenol
  • Glycerol