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Nat Cell Biol DOI:10.1038/ncb3080

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

Publication TypeJournal Article
Year of Publication2015
AuthorsKang, S, Tsai, LT, Zhou, Y, Evertts, A, Xu, S, Griffin, MJ, Issner, R, Whitton, HJ, Garcia, BA, Epstein, CB, Mikkelsen, TS, Rosen, ED
JournalNat Cell Biol
Date Published2015 Jan
Keywords3T3 Cells, Adipogenesis, Adipose Tissue, Animals, Base Sequence, Biological Transport, Cell Line, Dexamethasone, Diabetes Mellitus, Type 2, Epigenomics, Female, High-Throughput Nucleotide Sequencing, Histones, Insulin, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Obesity, Protein Binding, Receptors, Calcitriol, Receptors, Glucocorticoid, Sequence Analysis, DNA, Transcription Factor RelA, Transcription, Genetic, Tumor Necrosis Factor-alpha

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.


Alternate JournalNat. Cell Biol.
PubMed ID25503565
PubMed Central IDPMC4281178
Grant ListR01 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