Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis

Kang S, Tsai LT, Zhou Y, Evertts A, Xu S, Griffin MJ, Issner R, Whitton HJ, Garcia BA, Epstein CB, Mikkelsen TS, Rosen ED.

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.

Nat Cell Biol. 2015 Jan;17(1):44-56. doi: 10.1038/ncb3080. Epub 2014 Dec 15