MicroRNAs 103 and 107 regulate insulin sensitivity

Abstract

Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes1,2,3. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism4,5. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.

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Figure 1: Hepatic overexpression of miR-107 induces hyperglycaemia.
Figure 2: Silencing of miR-103 and miR-107 alleviates hyperglycaemia in diabetic mice.
Figure 3: Silencing of miR-103 decreases total fat by reducing adipocyte size.
Figure 4: Regulation of gene expression and insulin signalling by miR-103.

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Acknowledgements

We would like to thank F. Preitner and B. Thorens for the hyperinsulinaemic euglycaemic clamp studies. M.T. was supported by a fellowship from the Juvenile Diabetes Research Foundation International. The work was supported in part by the Swiss National Science Foundation (SNF, LiverX), the European Community (SIROCCO, ERC and MetaboloMirs) and the Leducq Foundation.

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M.T. and M.S. designed the experiments. M.T. performed the experiments and conducted the data analysis. J.H. and M.Z. performed the bioinformatic analysis. M.H.H. provided liver samples and participated in analysis of clinical data. B.B. synthesized antagomirs. A.A. provided liposomal formulations. M.T. and M.S. wrote the paper with input from all co-authors.

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Correspondence to Markus Stoffel.

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The authors declare no competing financial interests.

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Trajkovski, M., Hausser, J., Soutschek, J. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011). https://doi.org/10.1038/nature10112

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