Dnmt3a is an epigenetic mediator of adipose insulin resistance

TY - JOUR

T1 - Dnmt3a is an epigenetic mediator of adipose insulin resistance

AU - You, Dongjoo

AU - Nilsson, Emma

AU - Tenen, Danielle E.

AU - Lyubetskaya, Anna

AU - Lo, James C.

AU - Jiang, Rencong

AU - Deng, Jasmine

AU - Dawes, Brian A.

AU - Vaag, Allan

AU - Ling, Charlotte

AU - Rosen, Evan D.

AU - Kang, Sona

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.7554/eLife.30766

DO - 10.7554/eLife.30766

M3 - Journal article

C2 - 29091029

AN - SCOPUS:85041134844

SN - 2050-084X

VL - 6

JO - eLife

JF - eLife

M1 - e30766

ER -