1. Inhibition of Class I Histone Deacetylases Unveils a Mitochondrial Signature and Enhances Oxidative Metabolism in Skeletal Muscle and Adipose Tissue
- Author
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C. Godio, E. Gers, Alice Gualerzi, Elena Donetti, Nico Mitro, Donatella Caruso, Gaia Cermenati, Alessandra Ferrari, Enrique Saez, Dante Rotili, Antonello Mai, Uliano Guerrini, Andrea Galmozzi, Emma De Fabiani, Federica Gilardi, Sergio Valente, and Maurizio Crestani
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Histone Deacetylase 2 ,Adipose tissue ,Histone Deacetylase 1 ,Mitochondrion ,Biology ,Cell Line ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Molecular Targeted Therapy ,Obesity ,Epigenetics ,Muscle, Skeletal ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Myogenesis ,Histone deacetylase 2 ,Insulin ,Skeletal muscle ,Mice, Mutant Strains ,Mitochondria, Muscle ,3. Good health ,Histone Deacetylase Inhibitors ,Endocrinology ,medicine.anatomical_structure ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Mitochondrial biogenesis ,030220 oncology & carcinogenesis ,Commentary ,Anti-Obesity Agents ,Energy Metabolism - Abstract
Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I–specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I– but not a class II–selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1α action in skeletal muscle and enhanced PPARγ/PGC-1α signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I–selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes.
- Published
- 2013
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