title: The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Barts and the London, School of Medicine and Dentistry, Queen Mary University of London, London, UK; Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal. Electronic address: m.silvestre@qmul.ac.uk.
authors: M F P
authors: MF
authors: Silvestre
authors: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: B
authors: B
authors: Viollet
authors: Barts and the London, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: P W
authors: PW
authors: Caton
authors: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: J
authors: J
authors: Leclerc
authors: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: I
authors: I
authors: Sakakibara
authors: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: M
authors: M
authors: Foretz
authors: Barts and the London, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: M C
authors: MC
authors: Holness
authors: Barts and the London, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: M C
authors: MC
authors: Sugden
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics*; D000107:Acetylation; D000818:Animals; D031204:Caloric Restriction; D002478:Cells, Cultured; D004794:Enzyme Repression; D005260:Female; D018149:Glucose Intolerance; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D037761:Sirtuins
keywords: AMP protein kinase (AMPK); Calorie restriction; Glucose; Insulin; PGC-1α; SIRT1