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Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism

Nature Cell Biology volume 13, pages 434–446 (2011)Cite this article

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Abstract

The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143–145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143–ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.

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Figure 1: Dysregulated expression of the miR-143–145 cluster in insulin target tissues of obese and diabetic mice.
Figure 2: Conditional overexpression of miR-143 in mice.
Figure 3: Impaired glucose metabolism in miR-143-overexpressing mice.
Figure 4: Conditional overexpression of LacZ shRNA or miR-145 does not impair glucose homeostasis.
Figure 5: Conditional miR-143 overexpression impairs insulin-stimulated AKT activation in liver.
Figure 6: miR-143–145-deficient mice are protected from diet-induced insulin resistance and hepatic AKT inhibition.
Figure 7: In vivo SILAC identifies ORP8 as an miR-143 target.
Figure 8: Downregulation of ORP8 in cultured liver cells impairs insulin-stimulated AKT activation.

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Acknowledgements

We thank G. Schmall and T. Rayle for secretarial assistance and B. Hampel, S. Irlenbusch and J. Alber for technical assistance. We thank B. Schumacher, M. C. Vogt and P. Frommolt for support with the bioinformatics analysis of gene expression and SILAC data. This work was supported by the ZMMK (J.C.B.), the European Community’s Seventh Framework Programme (grant FP7/2007–2013, no 201608 to J.C.B.), the DFG (grant 1492-7 to J.C.B.), the Academy of Finland (grant 121457 to V.M.O.) and the Sigrid Juselius Foundation (V.M.O.).

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Authors and Affiliations

  1. Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC) University of Cologne, and Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Max Planck Institute for Neurological Research, Zülpicher Straße 47, D-50674 Cologne, Germany

    Sabine D. Jordan, Diana M. Willmes, Nora Redemann, F. Thomas Wunderlich & Jens C. Brüning

  2. Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany

    Markus Krüger, Thomas Böttger & Thomas Braun

  3. Phenotyping Facility of the Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), D-50674 Cologne, Germany

    Hella S. Brönneke

  4. Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, D-50674 Cologne, Germany

    Carsten Merkwirth

  5. Institute for Medical Microbiology, Immunology and Hygiene, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, D-50674 Cologne, Germany

    Hamid Kashkar

  6. Minerva Foundation Institute for Medical Research, Biomedicum, FI-00290 Helsinki, Finland

    Vesa M. Olkkonen

  7. TaconicArtemis Pharmaceuticals GmbH, D-51063 Cologne, Germany

    Jost Seibler

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  1. Sabine D. Jordan
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Contributions

S.D.J. and J.C.B. designed the research; S.D.J. carried out most of the experiments; M.K. carried out in vivo SILAC analyses; D.M.W. and N.R. provided extra technical assistance; F.T.W. helped to design cloning strategies; H.S.B. analysed energy expenditure in miR-143DOX mice; C.M. carried out luciferase assays; H.K. helped with lentivirus experiments; V.M.O. provided ORP8 antibody and shRNA ORP8 lentiviruses. T. Böttger and T. Braun provided miR143–145 knockout mice; J.S. in part generated miR-143DOX and miR-145DOX mice and provided LacZ shRNADOX mice. S.D.J. and J.C.B. wrote the manuscript. All authors participated in the interpretation of the data and production of the final manuscript.

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Correspondence to Jens C. Brüning.

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Jordan, S., Krüger, M., Willmes, D. et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol 13, 434–446 (2011). https://doi.org/10.1038/ncb2211

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