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

Kornfeld, Jan-Wilhelm; Baitzel, Catherina; Könner, A. Christine; Nicholls, Hayley T.; Vogt, Merly C.; Herrmanns, Karolin; Scheja, Ludger; Haumaitre, Cécile; Wolf, Anna M.; Knippschild, Uwe; Seibler, Jost; Cereghini, Silvia; Heeren, Joerg; Stoffel, Markus; Brüning, Jens C.
February 2013
Nature;2/7/2013, Vol. 494 Issue 7435, p111
Academic Journal
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 Leprdb/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.


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