NUCKS is a positive transcriptional regulator of insulin signaling

Cell Rep. 2014 Jun 26;7(6):1876-86. doi: 10.1016/j.celrep.2014.05.030. Epub 2014 Jun 12.


Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose / metabolism*
  • Glucose Intolerance / metabolism*
  • Homeostasis
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction
  • Transcriptional Activation


  • Insulin
  • NUCKS1 protein, human
  • Nucks protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Glucose

Associated data

  • GEO/GSE58100