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

TY - JOUR

T1 - The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions

AU - Silvestre, M.F.P.

AU - Viollet, B.

AU - Caton, P. W.

AU - Leclerc, J.

AU - Sakakibara, I.

AU - Foretz, M.

AU - Holness, M.C.

AU - Sugden, M.C.

PY - 2014/3/28

Y1 - 2014/3/28

N2 - 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 findingsCR-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.

AB - 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 findingsCR-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.

M3 - Article

SN - 0024-3205

SP - 55

EP - 60

JO - Life Sciences

JF - Life Sciences

ER -