Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.
Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.
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Nat Cell Biol
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R01 DK085171 / DK / NIDDK NIH HHS / United States
R01 ES017690 / ES / NIEHS NIH HHS / United States
R01085171 / PHS HHS / United States
R01 EY017690 / EY / NEI NIH HHS / United States
DP2OD007447 / OD / NIH HHS / United States
DP2 OD007447 / OD / NIH HHS / United States
T32 DK007516 / DK / NIDDK NIH HHS / United States
R01 DK087092 / DK / NIDDK NIH HHS / United States