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

Abstract 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 ±± p p 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.