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

The livers of obese mice and humans show increased levels of miR-802 resulting in impaired glucose tolerance and decreased insulin sensitivity through silencing of Hnf1b , revealing a novel pathway with potential relevance for type 2 diabetes. A microRNA linked to glucose metabolism Regulation of gene expression by microRNAs is known to have a role in various diseases, including type 2 diabetes. Here it is shown that the level of miR-802 is increased in the livers of obese mice and humans. Overexpression of miR-802 results in impaired glucose tolerance and insulin actions, whereas its reduction improves glucose tolerance and insulin sensitivity. It is further shown that miR-802-dependent silencing of Hnf1b (also called Tcf2 ) mediates these effects. This work suggests that both miR-802 and Hnf1b are potential therapeutic targets. 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 1 , 2 , 3 . 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.