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Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signalling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional cofactors, and chromatin\u2010modifying enzymes will be considered. Well\u2010studied examples of the first include PPAR\u2010\u03b3 in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin\u2010sensitive tissues. These proteins work in concert with cofactors such as\n                    <jats:styled-content style=\"fixed-case\">PGC<\/jats:styled-content>\n                    \u20101\u03b1 and\n                    <jats:styled-content style=\"fixed-case\">CRTC<\/jats:styled-content>\n                    2, and chromatin\u2010modifying enzymes including\n                    <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\n                    methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin\u2010stimulated glucose uptake, gluconeogenesis or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a noncoding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small\u2010molecule inhibitors and activators of these factors and their related pathways.\n                  <\/jats:p>","DOI":"10.1111\/joim.12547","type":"journal-article","created":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T04:44:53Z","timestamp":1476420293000},"page":"443-456","source":"Crossref","is-referenced-by-count":34,"title":["Epigenomic and transcriptional control of insulin resistance"],"prefix":"10.1111","volume":"280","author":[{"given":"E. 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