Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

MicroRNAs 103 and 107 regulate insulin sensitivity


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Kahn, C. R. Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes. Exp. Diabesity Res. 4, 169–182 (2003)

    Article  Google Scholar 

  2. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006)

    Article  CAS  Google Scholar 

  3. Muoio, D. M. & Newgard, C. B. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nature Rev. Mol. Cell Biol. 9, 193–205 (2008)

    Article  CAS  Google Scholar 

  4. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009)

    Article  CAS  Google Scholar 

  5. Krützfeldt, J. & Stoffel, M. MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 4, 9–12 (2006)

    Article  Google Scholar 

  6. Herrera, B. M. et al. Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53, 1099–1109 (2010)

    Article  CAS  Google Scholar 

  7. Anderson, N. & Borlak, J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol. Rev. 60, 311–357 (2008)

    Article  CAS  Google Scholar 

  8. Krützfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005)

    Article  ADS  Google Scholar 

  9. Esau, C. et al. MicroRNA-143 regulates adipocyte differentiation. J. Biol. Chem. 279, 52361–52365 (2004)

    Article  CAS  Google Scholar 

  10. Kajimoto, K., Naraba, H. & Iwai, N. MicroRNA and 3T3–L1 pre-adipocyte differentiation. RNA 12, 1626–1632 (2006)

    Article  CAS  Google Scholar 

  11. Ortega, F. J. et al. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS ONE 5, e9022 (2010)

    Article  ADS  Google Scholar 

  12. Sun, T., Fu, M., Bookout, A. L., Kliewer, S. A. & Mangelsdorf, D. J. MicroRNA let-7 regulates 3T3–L1 adipogenesis. Mol. Endocrinol. 23, 925–931 (2009)

    Article  CAS  Google Scholar 

  13. Xie, H., Lim, B. & Lodish, H. F. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 58, 1050–1057 (2009)

    Article  CAS  Google Scholar 

  14. Goossens, G. H. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol. Behav. 94, 206–218 (2008)

    Article  CAS  Google Scholar 

  15. Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med. 7, 941–946 (2001)

    Article  CAS  Google Scholar 

  16. Rothberg, K. G. et al. Caveolin, a protein component of caveolae membrane coats. Cell 68, 673–682 (1992)

    Article  CAS  Google Scholar 

  17. Nystrom, F. H., Chen, H., Cong, L. N., Li, Y. & Quon, M. J. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol. Endocrinol. 13, 2013–2024 (1999)

    Article  CAS  Google Scholar 

  18. Yamamoto, M. et al. Caveolin is an activator of insulin receptor signaling. J. Biol. Chem. 273, 26962–26968 (1998)

    Article  CAS  Google Scholar 

  19. Otsu, K. et al. Caveolin gene transfer improves glucose metabolism in diabetic mice. Am. J. Physiol. Cell Physiol. 298, C450–c456 (2009)

    Article  Google Scholar 

  20. Cohen, A. W. et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am. J. Physiol. Cell Physiol. 285, C222–C235 (2003)

    Article  CAS  Google Scholar 

  21. Cohen, A. W., Combs, T. P., Scherer, P. E. & Lisanti, M. P. Role of caveolin and caveolae in insulin signaling and diabetes. Am. J. Physiol. Endocrinol. Metab. 285, E1151–E1160 (2003)

    Article  CAS  Google Scholar 

  22. Parton, R. G. & Simons, K. The multiple faces of caveolae. Nature Rev. Mol. Cell Biol. 8, 185–194 (2007)

    Article  CAS  Google Scholar 

  23. Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nature Biotechnol. 28, 172–176 (2010)

    Article  CAS  Google Scholar 

  24. Hansen, L. H., Madsen, B., Teisner, B., Nielsen, J. H. & Billestrup, N. Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. Mol. Endocrinol. 12, 1140–1149 (1998)

    Article  CAS  Google Scholar 

  25. Tozzo, E., Shepherd, P. R., Gnudi, L. & Kahn, B. B. Transgenic GLUT-4 overexpression in fat enhances glucose metabolism: preferential effect on fatty acid synthesis. Am. J. Physiol. 268, E956–E964 (1995)

    CAS  PubMed  Google Scholar 

  26. Minehira, K. et al. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J. Lipid Res. 49, 2038–2044 (2008)

    Article  CAS  Google Scholar 

  27. Preitner, F., Mody, N., Graham, T. E., Peroni, O. D. & Kahn, B. B. Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 297, E1420–E1429 (2009)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Markus Stoffel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Tables 1-2 and Supplementary Figures 1-9 with legends. (PDF 930 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research