1. The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions
- Author
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M.C. Holness, Marc Foretz, Iori Sakakibara, Marta P. Silvestre, Mary C. Sugden, Paul W. Caton, Benoit Viollet, and J. Leclerc
- Subjects
medicine.medical_specialty ,Calorie ,medicine.medical_treatment ,Calorie restriction ,AMP-Activated Protein Kinases ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Impaired glucose tolerance ,Mice ,Internal medicine ,Glucose Intolerance ,medicine ,Animals ,Sirtuins ,Myocyte ,General Pharmacology, Toxicology and Pharmaceutics ,Muscle, Skeletal ,Protein kinase A ,Cells, Cultured ,Caloric Restriction ,Mice, Knockout ,Insulin ,AMPK ,Skeletal muscle ,Acetylation ,General Medicine ,medicine.disease ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Endocrinology ,medicine.anatomical_structure ,Female ,Enzyme Repression ,Protein Processing, Post-Translational ,Signal Transduction ,Transcription Factors - Abstract
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.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).CR-AMPKα1/2(-/-) displayed impaired glucose tolerance (*p0.05), in association with down-regulated SIRT1 and PGC-1α expression (300% vs. CR-WT, (±±)p0.01). Moreover, AMPK activity was decreased following SIRT1 inhibition in L6 cells (~0.5-fold vs. control, *p0.05).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.
- Published
- 2014