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

Nature volume 494, pages 111–115 (2013)Cite this article

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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 metabolism1,2,3. 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 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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Figure 1: miR-802 expression is increased in obese mice and humans.
Figure 2: Overexpression of miR-802 impairs insulin action and glucose metabolism.
Figure 3: Suppression of miR-802 expression improves obesity-associated insulin resistance and glucose intolerance.
Figure 4: Silencing of the miR-802 target Hnf1b impairs insulin action and glucose metabolism.

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Gene Expression Omnibus

Data deposits

Gene expression data was deposited with Gene Expression Omnibus (GEO) under accession number GSE42188.

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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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Authors and Affiliations

  1. Max-Planck-Institute for Neurological Research, Gleueler Strasse 50a, 50931 Cologne, Germany ,

    Jan-Wilhelm Kornfeld, Catherina Baitzel, A. Christine Könner, Hayley T. Nicholls, Merly C. Vogt & Jens C. Brüning

  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Zülpicher Strasse 47a, 50674 Cologne, Germany ,

    Jan-Wilhelm Kornfeld, Catherina Baitzel, A. Christine Könner, Hayley T. Nicholls, Merly C. Vogt & Jens C. Brüning

  3. Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne and Center for Molecular Medicine Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany,

    Jan-Wilhelm Kornfeld, Catherina Baitzel, A. Christine Könner, Hayley T. Nicholls, Merly C. Vogt & Jens C. Brüning

  4. Swiss Federal Institute of Technology (ETH Zurich), Institute of Molecular Health Science, Schafmattstrasse 22, 8093 Zurich, Switzerland ,

    Karolin Herrmanns & Markus Stoffel

  5. Department of Biochemistry and Molecular Cell Biology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany,

    Ludger Scheja & Joerg Heeren

  6. INSERM U 969, 9 Quai Saint Bernard, 75005 Paris, France ,

    Cécile Haumaitre & Silvia Cereghini

  7. CNRS Université Pierre et Marie Curie UMR7622, 9 Quai Saint Bernard, 75005 Paris, France ,

    Cécile Haumaitre & Silvia Cereghini

  8. Department of General and Visceral Surgery, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany,

    Anna M. Wolf & Uwe Knippschild

  9. TaconicArtemis GmbH, Neurather Ring 1, 51063 Cologne, Germany ,

    Jost Seibler

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  1. Jan-Wilhelm Kornfeld
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  15. Jens C. Brüning
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Contributions

J.C.B. and J.-W.K. conceived the study and wrote the manuscript. J.-W.K. and C.B. performed most experiments. A.C.K. performed the euglycaemic–hyperinsulinaemic clamp experiments. H.T.N. performed adenoviral treatments of mice. M.C.V. contributed to bioinformatical analyses. K.H. and M.S. analysed miR-802 expression in murine tissues. J.S. aided in the generation of miR-802 transgenic mice. C.H. and S.C. provided tissues and analysed glucose metabolism in Hnf1b+/− mice. A.M.W., U.K., L.S. and J.H. provided and analysed human liver explants for miR-802 expression. All authors approved the manuscript.

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Correspondence to Jens C. Brüning.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-11, Supplementary Tables 1-2, Supplementary Methods and additional references. (PDF 1835 kb)

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Kornfeld, JW., Baitzel, C., Könner, A. et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494, 111–115 (2013). https://doi.org/10.1038/nature11793

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