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


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

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


  1. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011)

    Article  CAS  Google Scholar 

  3. Glass, C. K. & Olefsky, J. M. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 15, 635–645 (2012)

    Article  CAS  Google Scholar 

  4. Jordan, S. D. et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nature Cell Biol. 13, 434–446 (2011)

    Article  CAS  Google Scholar 

  5. Zhou, B. et al. Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 55, 2032–2043

    Article  CAS  Google Scholar 

  6. Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011)

    Article  CAS  Google Scholar 

  7. Nakanishi, N. et al. The up-regulation of microRNA-335 is associated with lipid metabolism in liver and white adipose tissue of genetically obese mice. Biochem. Biophys. Res. Commun. 385, 492–496 (2009)

    Article  CAS  Google Scholar 

  8. Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nature Genet. 17, 384–385 (1997)

    Article  CAS  Google Scholar 

  9. Han, X. et al. Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in type 2 diabetes in a Chinese population. BMC Med. Genet. 11, 81 (2010)

    Article  Google Scholar 

  10. Barbacci, E. et al. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 126, 4795–4805 (1999)

    CAS  PubMed  Google Scholar 

  11. Lindner, T. H. et al. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1β. Hum. Mol. Genet. 8, 2001–2008 (1999)

    Article  CAS  Google Scholar 

  12. Wen, J. et al. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. PLoS ONE 5, e9153 (2010)

    Article  ADS  Google Scholar 

  13. Haumaitre, C. et al. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1β/MODY5 mutations. Hum. Mol. Genet. 15, 2363–2375 (2006)

    Article  CAS  Google Scholar 

  14. Bellanné-Chantelot, C. et al. Clinical spectrum associated with hepatocyte nuclear factor-1β mutations. Ann. Intern. Med. 140, 510–517 (2004)

    Article  Google Scholar 

  15. Ma, Z. et al. Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3. Proc. Natl Acad. Sci. USA 104, 20386–20391 (2007)

    Article  ADS  CAS  Google Scholar 

  16. Howard, J. K. & Flier, J. S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17, 365–371 (2006)

    Article  CAS  Google Scholar 

  17. Ueki, K., Kondo, T., Tseng, Y. H. & Kahn, C. R. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc. Natl Acad. Sci. USA 101, 10422–10427 (2004)

    Article  ADS  CAS  Google Scholar 

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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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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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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).

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