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Elife. 2017 Nov 1;6. pii: e30766. doi: 10.7554/eLife.30766.

Dnmt3a is an epigenetic mediator of adipose insulin resistance.

Author information

1
Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States.
2
Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
3
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States.
4
Broad Institute of Harvard and MIT, Cambridge, United States.
5
Weill Cornell Medical College, New York, United States.
6
Diabetes and Metabolism, Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
7
Early Clinical Development, AstraZeneca, Innovative Medicines, Göteborg, Sweden.

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.

KEYWORDS:

adipocyte; cell biology; epigenetic; insulin resistance; mouse

PMID:
29091029
PMCID:
PMC5730374
DOI:
10.7554/eLife.30766
[Indexed for MEDLINE]
Free PMC Article

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