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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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.).
The authors declare no competing financial interests.
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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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