Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b

Nature. 2013 Feb 7;494(7435):111-5. doi: 10.1038/nature11793.


Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Gene Silencing*
  • Gluconeogenesis
  • Glucose / biosynthesis
  • Glucose / metabolism*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Hepatocyte Nuclear Factor 1-beta / deficiency*
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 1-beta / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Liver / metabolism
  • Mice
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Obesity / genetics*
  • Signal Transduction


  • Hnf1b protein, mouse
  • Insulin
  • MIRN802 microRNA, human
  • MIRN802 microRNA, mouse
  • MicroRNAs
  • Hepatocyte Nuclear Factor 1-beta
  • Glucose

Associated data

  • GEO/GSE42188