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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adipogenesis / genetics
  • Adipose Tissue / metabolism
  • Animals
  • Base Sequence
  • Biological Transport / drug effects
  • Cell Line
  • Dexamethasone / pharmacology*
  • Diabetes Mellitus, Type 2 / pathology
  • Epigenomics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Histones / genetics
  • Histones / metabolism
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / pathology
  • Protein Binding
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Receptors, Glucocorticoid / metabolism*
  • Sequence Analysis, DNA
  • Transcription Factor RelA / genetics
  • Transcription, Genetic / genetics
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Histones
  • Insulin
  • Receptors, Calcitriol
  • Receptors, Glucocorticoid
  • Rela protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Dexamethasone

Associated data

  • GEO/GSE58491
  • GEO/GSE62635