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

Jan Wilhelm Kornfeld*, Catherina Baitzel, A. Christine Könner, Hayley T. Nicholls, Merly C. Vogt, Karolin Herrmanns, Ludger Scheja, Cécile Haumaitre, Anna M. Wolf, Uwe Knippschild, Jost Seibler, Silvia Cereghini, Joerg Heeren, Markus Stoffel, Jens C. Brüning


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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.

Udgave nummer7435
Sider (fra-til)111-115
StatusUdgivet - 7. feb. 2013
Udgivet eksterntJa

Bibliografisk note

Funding Information:
Acknowledgements J.-W.K. was supported by stipends from EMBO and CECAD. S.C. received funds from INSERM, CNRS and EU FP7 (Marie Curie Initial Training Network BOLD). This work was in part supported by ERC grant ‘Metabolomirs’ (to M.S.), by a grant to J.H. by the DFG (SFB 841) and DFG funding to J.C.B. (Br1492-7). We thank D. Wagner-Stippich, J. Alber, P. Scholl and B. Hampel for technical assistance.


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