title: Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b.
abstract: 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.
authors: Max-Planck-Institute for Neurological Research, Gleueler Strasse 50a, 50931 Cologne, Germany.
authors: Jan-Wilhelm
authors: JW
authors: Kornfeld
authors: Catherina
authors: C
authors: Baitzel
authors: A Christine
authors: AC
authors: Könner
authors: Hayley T
authors: HT
authors: Nicholls
authors: Merly C
authors: MC
authors: Vogt
authors: Karolin
authors: K
authors: Herrmanns
authors: Ludger
authors: L
authors: Scheja
authors: Cécile
authors: C
authors: Haumaitre
authors: Anna M
authors: AM
authors: Wolf
authors: Uwe
authors: U
authors: Knippschild
authors: Jost
authors: J
authors: Seibler
authors: Silvia
authors: S
authors: Cereghini
authors: Joerg
authors: J
authors: Heeren
authors: Markus
authors: M
authors: Stoffel
authors: Jens C
authors: JC
authors: Brüning
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C496496:Hnf1b protein, mouse; D007328:Insulin; C552280:MIRN802 microRNA, human; C560526:MIRN802 microRNA, mouse; D035683:MicroRNAs; D051539:Hepatocyte Nuclear Factor 1-beta; D005947:Glucose
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