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Inhibition of class i histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue

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Overview

authors

  • Galmozzi, A.
  • Mitro, N.
  • Ferrari, A.
  • Gers, E.
  • Gilardi, F.
  • Godio, C.
  • Cermenati, G.
  • Gualerzi, A.
  • Donetti, E.
  • Rotili, D.
  • Guerrini, U.
  • Caruso, D.
  • Mai, A.
  • Saez, Enrique
  • De Fabiani, E.
  • Crestani, M.
  • Valente, Sergio

publication date

  • March 2013

journal

  • Diabetes  Journal

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-1?, 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-1? action in skeletal muscle and enhanced PPAR?/PGC-1? 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.
  • 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.

subject areas

  • Adipose Tissue
  • Animals
  • Anti-Obesity Agents
  • Cell Line
  • Cells, Cultured
  • Diabetes Mellitus, Type 2
  • Energy Metabolism
  • Gene Expression Regulation
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylase Inhibitors
  • Hypoglycemic Agents
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mitochondria, Muscle
  • Molecular Targeted Therapy
  • Muscle, Skeletal
  • Obesity
  • Random Allocation
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Identity

PubMed Central ID

  • PMC3581211

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/db12-0548

PubMed ID

  • 23069623
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Additional Document Info

start page

  • 732

end page

  • 742

volume

  • 62

issue

  • 3

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