Inhibition of Class I Histone Deacetylases Unveils a Mitochondrial Signature and Enhances Oxidative Metabolism in Skeletal Muscle and Adipose Tissue

被引:200
作者
Galmozzi, Andrea [1 ]
Mitro, Nico [2 ]
Ferrari, Alessandra [1 ]
Gers, Elise [1 ]
Gilardi, Federica [1 ]
Godio, Cristina [1 ]
Cermenati, Gaia [2 ]
Gualerzi, Alice [3 ]
Donetti, Elena [3 ]
Rotili, Dante [4 ]
Valente, Sergio [4 ]
Guerrini, Uliano [5 ]
Caruso, Donatella [1 ]
Mai, Antonello [4 ]
Saez, Enrique [6 ,7 ]
De Fabiani, Emma [1 ]
Crestani, Maurizio [1 ]
机构
[1] Univ Milan, Lab Giovanni Galli Biochim & Biol Mol Metab & Spe, Milan, Italy
[2] Univ Milan, Lab Giovanni Armenise Harvard Fdn, Milan, Italy
[3] Univ Milan, Lab Immunoistochim Epiteli, Dipartimento Morfol Umana & Sci Biomed Citta Stud, Milan, Italy
[4] Univ Roma La Sapienza, Inst Pasteur, Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, Rome, Italy
[5] Univ Milan, Dipartimento Sci Farmacol & Biomol, Unit Magnet Resonance Imaging, Milan, Italy
[6] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
[7] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
基金
美国国家卫生研究院;
关键词
PPAR-GAMMA ACTIVATION; PHOSPHORYLATION; EPIGENETICS; ADIPOCYTES; EXPRESSION; MECHANISM; DELETION; COMPLEX; OBESITY; HDAC3;
D O I
10.2337/db12-0548
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-l alpha, 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-la action in skeletal muscle and enhanced PPAR gamma/PGC-l alpha signaling in adipose tissue. In vivo ChlP 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. Diabetes 62:732-742, 2013
引用
收藏
页码:732 / 742
页数:11
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