Dnmt3a is an epigenetic mediator of adipose insulin resistance

  1. Dongjoo You
  2. Emma Nilsson
  3. Danielle E Tenen
  4. Anna Lyubetskaya
  5. James Lo
  6. Rencong Jiang
  7. Jasmine Deng
  8. Brian A Dawes
  9. Allan Vaag
  10. Charlotte Ling
  11. Evan D Rosen  Is a corresponding author
  12. Sona Kang  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Lund University, Sweden
  3. Beth Israel Deaconess Medical Center, United States
  4. Broad Institute, United States
  5. Weill Cornell Medical College, United States
  6. University of Copenhagen, Denmark

Abstract

Insulin resistance results from an intricate interaction between genetic make-up and environment, and thus may be orchestrated by epigenetic mechanisms like DNA methylation. Here, we demonstrate that DNA methyltransferase 3a (Dnmt3a) is both necessary and sufficient to mediate insulin resistance in cultured mouse and human adipocytes. Furthermore, adipose-specific Dnmt3a knock-out mice are protected from diet-induced insulin resistance and glucose intolerance without accompanying changes in adiposity. Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region. Consistent with this, Fgf21 can rescue Dnmt3a-mediated insulin resistance, and DNA methylation at the FGF21 locus was elevated in human subjects with diabetes and correlated negatively with expression of FGF21 in human adipose tissue. Taken together, our data demonstrate that adipose Dnmt3a is a novel epigenetic mediator of insulin resistance in vitro and in vivo.

Article and author information

Author details

  1. Dongjoo You

    Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Emma Nilsson

    Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Danielle E Tenen

    Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna Lyubetskaya

    Broad Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. James Lo

    Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Rencong Jiang

    Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jasmine Deng

    Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Brian A Dawes

    Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Allan Vaag

    Diabetes and Metabolism, Department of Endocrinology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  10. Charlotte Ling

    Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  11. Evan D Rosen

    Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
    For correspondence
    erosen@bidmc.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  12. Sona Kang

    Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States
    For correspondence
    kangs@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9831-677X

Funding

American Heart Association (15SDG25240017)

  • Sona Kang

National Institutes of Health (102173)

  • Evan D Rosen

National Institutes of Health (102170)

  • Evan D Rosen

National Institutes of Health (85171)

  • Evan D Rosen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal work was approved by the BIDMC IACUC (056-2017) and/or the UC Berkeley ACUC (AUP-2015-08-7887).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Publication history

  1. Received: July 26, 2017
  2. Accepted: October 29, 2017
  3. Accepted Manuscript published: November 1, 2017 (version 1)
  4. Version of Record published: December 14, 2017 (version 2)

Copyright

© 2017, You et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Dongjoo You
  2. Emma Nilsson
  3. Danielle E Tenen
  4. Anna Lyubetskaya
  5. James Lo
  6. Rencong Jiang
  7. Jasmine Deng
  8. Brian A Dawes
  9. Allan Vaag
  10. Charlotte Ling
  11. Evan D Rosen
  12. Sona Kang
(2017)
Dnmt3a is an epigenetic mediator of adipose insulin resistance
eLife 6:e30766.
https://doi.org/10.7554/eLife.30766
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