Cell Biology

Dnmt3a is an epigenetic mediator of adipose insulin resistance

University of California, Berkeley, United States
Lund University, Sweden
Beth Israel Deaconess Medical Center, United States
Broad Institute, United States
Weill Cornell Medical College, United States
University of Copenhagen, Denmark

Research Article Nov 1, 2017

Cited 15
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Cite this article as: eLife 2017;6:e30766 doi: 10.7554/eLife.30766

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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.

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Author details

Dongjoo You

Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Emma Nilsson

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden

Competing interests
The authors declare that no competing interests exist.
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.
Anna Lyubetskaya

Broad Institute, Boston, United States

Competing interests
The authors declare that no competing interests exist.
James Lo

Weill Cornell Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Rencong Jiang

Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Jasmine Deng

Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
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.
Allan Vaag

Diabetes and Metabolism, Department of Endocrinology, University of Copenhagen, Copenhagen, Denmark

Competing interests
The authors declare that no competing interests exist.
Charlotte Ling

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden

Competing interests
The authors declare that no competing interests exist.
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.
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.

"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

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

Publication history

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

Copyright

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.