Skip to main content

Thank you for visiting nature.com. 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.

A central role for JNK in obesity and insulin resistance

Nature volume 420, pages 333–336 (2002)Cite this article

An Author Correction to this article was published on 16 June 2023

This article has been updated

Abstract

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood1. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells2 and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes3,4. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Total JNK activity and development of diet-induced obesity.
Figure 2: Adipose tissue morphology and adiposity in Jnk1 -/- mice and wild-type controls.
Figure 3: Metabolic effects of JNK1-deficiency.
Figure 4: JNK activity and insulin signalling in JNK1-deficient mice.

Change history

References

  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  PubMed  Google Scholar 

  2. Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. F. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275, 9047–9054 (2000)

    Article  CAS  PubMed  Google Scholar 

  3. Sethi, J. K. & Hotamisligil, G. S. The role of TNF alpha in adipocyte metabolism. Semin. Cell. Dev. Biol. 10, 19–29 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997)

    Article  CAS  PubMed  Google Scholar 

  5. Must, A. et al. The disease burden associated with overweight and obesity. J. Am. Med. Assoc. 282, 1523–1529 (1999)

    Article  CAS  Google Scholar 

  6. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Hotamisligil, G. S. & Spiegelman, B. M. Diabetes Mellitus (eds LeRoith, D., Taylor, S. I. & Olefsky, J. M.) 651–658 (Lippincott Williams & Wilkins, Philadelphia, 2000)

    Google Scholar 

  8. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Shin, E. A. et al. Arachidonic acid induces the activation of the stress-activated protein kinase, membrane ruffling and H2O2 production via a small GTPase Rac1. FEBS Lett. 452, 355–359 (1999)

    Article  CAS  PubMed  Google Scholar 

  10. Rizzo, M. T., Leaver, A. H., Yu, W. M. & Kovacs, R. J. Arachidonic acid induces mobilization of calcium stores and c-jun gene expression: evidence that intracellular calcium release is associated with c-jun activation. Prostaglandins Leukot. Essent. Fatty Acids 60, 187–198 (1999)

    Article  CAS  PubMed  Google Scholar 

  11. Kyriakis, J. M. & Avruch, J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J. Biol. Chem. 271, 24313–24316 (1996)

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. Berg, A. H., Combs, T. P., Du, X., Brownlee, M. & Scherer, P. E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Med. 7, 947–953 (2001)

    Article  CAS  PubMed  Google Scholar 

  14. Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Kim, K. H., Lee, K., Moon, Y. S. & Sul, H. S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J. Biol. Chem. 276, 11252–11256 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Davis, R. J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000)

    Article  CAS  PubMed  Google Scholar 

  17. Dong, C. et al. Defective T cell differentiation in the absence of Jnk1. Science 282, 2092–2095 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Sabapathy, K. et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr. Biol. 9, 116–125 (1999)

    Article  CAS  PubMed  Google Scholar 

  19. Sabapathy, K. et al. c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J. Exp. Med. 193, 317–328 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shulman, G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hotamisligil, G. H. et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271, 665–668 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Griffin, M. E. et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48, 1270–1274 (1999)

    Article  CAS  PubMed  Google Scholar 

  23. Waeber, G. et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nature Genet. 24, 291–295 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Hibi, M., Lin, A., Smeal, T., Minden, A. & Karin, M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7, 2135–2148 (1993)

    Article  CAS  Google Scholar 

  25. Uysal, K. T., Scheja, L., Wiesbrock, S. M., Bonner-Weir, S. & Hotamisligil, G. S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141, 3388–3396 (2000)

    Article  CAS  PubMed  Google Scholar 

  26. Bennett, B. L. et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl Acad. Sci. USA 98, 13681–13686 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is in part supported by grants from the National Institutes of Health (M.K. and G.S.H.) and the Pew Foundation (G.S.H.).

Author information

Author notes

  1. Jiro Hirosumi, Gürol Tuncman, Lufen Chang and Michael Karin: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Massachusetts, 02115, Boston, USA

    Jiro Hirosumi, Gürol Tuncman, Cem Z. Görgün, K. Teoman Uysal, Kazuhisa Maeda & Gökhan S. Hotamisligil

  2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California , School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, San Diego, USA

    Lufen Chang & Michael Karin

Authors
  1. Jiro Hirosumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gürol Tuncman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lufen Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cem Z. Görgün
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Teoman Uysal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhisa Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Karin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gökhan S. Hotamisligil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gökhan S. Hotamisligil.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hirosumi, J., Tuncman, G., Chang, L. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002). https://doi.org/10.1038/nature01137

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01137

This article is cited by

Comments

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.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing