Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1

Cell Metab. 2010 Feb 3;11(2):113-24. doi: 10.1016/j.cmet.2009.12.010.

Abstract

Fyn null mice display reduced adiposity associated with increased fatty acid oxidation, energy expenditure, and activation of the AMP-dependent protein kinase (AMPK) in skeletal muscle and adipose tissue. The acute pharmacological inhibition of Fyn kinase activity with SU6656 in wild-type mice reproduces these metabolic effects and induced a specific reduction in fat mass with no change in lean mass. LKB1, the main upstream AMPK kinase (AMPKK) in peripheral tissues, was redistributed from the nucleus into the cytoplasm of cells treated with SU6656 and in cells expressing a kinase-deficient, but not a constitutively kinase-active, Fyn mutant. Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues, and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. These data demonstrate a crosstalk between Fyn tyrosine kinase and the AMPK energy-sensing pathway, through Fyn-dependent regulation of the AMPK upstream activator LKB1.

Publication types

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

MeSH terms

  • Animals
  • Body Weight* / drug effects
  • Cell Line
  • Energy Metabolism* / drug effects
  • Gene Knockout Techniques
  • Indoles / administration & dosage
  • Indoles / pharmacology
  • Lipid Metabolism / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / analysis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-fyn / antagonists & inhibitors
  • Proto-Oncogene Proteins c-fyn / genetics
  • Proto-Oncogene Proteins c-fyn / metabolism*
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology
  • Tyrosine / metabolism*

Substances

  • Indoles
  • SU 6656
  • Sulfonamides
  • Tyrosine
  • Stk11 protein, mouse
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • Protein-Serine-Threonine Kinases