Dnmt3a is an epigenetic mediator of adipose insulin resistance
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Dnmt3a is an epigenetic mediator of adipose insulin resistance. / You, Dongjoo; Nilsson, Emma; Tenen, Danielle E.; Lyubetskaya, Anna; Lo, James C.; Jiang, Rencong; Deng, Jasmine; Dawes, Brian A.; Vaag, Allan; Ling, Charlotte; Rosen, Evan D.; Kang, Sona.
In: eLife, Vol. 6, e30766, 2017.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 6
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e30766
ER -
ID: 196141417