AMP-Activated Protein Kinase Regulates GLUT4 Transcription by Phosphorylating Histone Deacetylase 5

  1. Mark Hargreaves1
  1. 1Department of Physiology, The University of Melbourne, Melbourne, Australia
  2. 2School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia
  3. 3St. Vincent’s Institute, Fitzroy, Australia
  4. 4CSIRO Molecular and Health Technologies, Parkville, Australia
  1. Address correspondence and reprint requests to Sean McGee, Department of Physiology, The University of Melbourne, 3010, Australia. E-mail: slmcgee{at}unimelb.edu.au

Abstract

OBJECTIVE—Insulin resistance associated with obesity and diabetes is ameliorated by specific overexpression of GLUT4 in skeletal muscle. The molecular mechanisms regulating skeletal muscle GLUT4 expression remain to be elucidated. The purpose of this study was to examine these mechanisms.

RESEARCH DESIGN AND METHODS AND RESULTS—Here, we report that AMP-activated protein kinase (AMPK) regulates GLUT4 transcription through the histone deacetylase (HDAC)5 transcriptional repressor. Overexpression of HDAC5 represses GLUT4 reporter gene expression, and HDAC inhibition in human primary myotubes increases endogenous GLUT4 gene expression. In vitro kinase assays, site-directed mutagenesis, and site-specific phospho-antibodies establish AMPK as an HDAC5 kinase that targets S259 and S498. Constitutively active but not dominant-negative AMPK and 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) treatment in human primary myotubes results in HDAC5 phosphorylation at S259 and S498, association with 14-3-3 isoforms, and H3 acetylation. This reduces HDAC5 association with the GLUT4 promoter, as assessed through chromatin immunoprecipitation assays and HDAC5 nuclear export, concomitant with increases in GLUT4 gene expression. Gene reporter assays also confirm that the HDAC5 S259 and S498 sites are required for AICAR induction of GLUT4 transcription.

CONCLUSIONS—These data reveal a signal transduction pathway linking cellular energy charge to gene transcription directed at restoring cellular and whole-body energy balance and provide new therapeutic targets for the treatment and management of insulin resistance and type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 9 January 2007. DOI: 10.2337/db07-0843.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0843.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received June 20, 2007.
    • Accepted January 1, 2008.
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  1. Diabetes vol. 57 no. 4 860-867
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