Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue.
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.
Laboratorio Giovanni Galli di Biochimica e Biologia Molecolare del Metabolismo e Spettrometria di Massa, Università degli Studi di Milano, Milan, Italy.
Andrea
A
Galmozzi
Nico
N
Mitro
Alessandra
A
Ferrari
Elise
E
Gers
Federica
F
Gilardi
Cristina
C
Godio
Gaia
G
Cermenati
Alice
A
Gualerzi
Elena
E
Donetti
Dante
D
Rotili
Sergio
S
Valente
Uliano
U
Guerrini
Donatella
D
Caruso
Antonello
A
Mai
Enrique
E
Saez
Emma
E
De Fabiani
Maurizio
M
Crestani
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D058990:Molecular Targeted Therapy; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation
D019440:Anti-Obesity Agents; D056572:Histone Deacetylase Inhibitors; D007004:Hypoglycemic Agents; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2