The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions

Life Sci. 2014 Mar 28;100(1):55-60. doi: 10.1016/j.lfs.2014.01.080. Epub 2014 Feb 13.


Aims: SIRT1 and AMP-activated protein kinase (AMPK) share common activators, actions and target molecules. Previous studies have suggested that a putative SIRT1-AMPK regulatory network could act as the prime initial sensor for calorie restriction-induced adaptations in skeletal muscle-the major site of insulin-stimulated glucose disposal. Our study aimed to investigate whether a feedback loop exists between AMPK and SIRT1 in skeletal muscle and how this may be involved glucose tolerance.

Main methods: To investigate this, we used skeletal muscle-specific AMPKα1/2 knockout mice (AMPKα1/2(-/-)) fed ad libitum (AL) or a 30% calorie restricted (CR) diet and L6 rat myoblasts incubated with SIRT1 inhibitor (EX527).

Key findings: CR-AMPKα1/2(-/-) displayed impaired glucose tolerance (*p<0.05), in association with down-regulated SIRT1 and PGC-1α expression (<300% vs. CR-WT, (±±)p<0.01). Moreover, AMPK activity was decreased following SIRT1 inhibition in L6 cells (~0.5-fold vs. control, *p<0.05).

Significance: This study demonstrates that skeletal muscle-specific AMPK deficiency impairs the beneficial effects of CR on glucose tolerance and that these effects may be dependent on reduced SIRT1 levels.

Keywords: AMP protein kinase (AMPK); Calorie restriction; Glucose; Insulin; PGC-1α; SIRT1.

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics*
  • Acetylation
  • Animals
  • Caloric Restriction
  • Cells, Cultured
  • Enzyme Repression
  • Female
  • Glucose Intolerance*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / enzymology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Sirtuins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinases
  • Sirtuins