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A central role for JNK in obesity and insulin resistance

Naturevolume 420pages333336 (2002) | Download Citation

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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.

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References

  1. 1

    Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001)

  2. 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)

  3. 3

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

  4. 4

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

  5. 5

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

  6. 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)

  7. 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)

  8. 8

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

  9. 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)

  10. 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)

  11. 11

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

  12. 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)

  13. 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)

  14. 14

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

  15. 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)

  16. 16

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

  17. 17

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

  18. 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)

  19. 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)

  20. 20

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

  21. 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)

  22. 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)

  23. 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)

  24. 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)

  25. 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)

  26. 26

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

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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.).

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Author notes

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

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

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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Gökhan S. Hotamisligil.

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https://doi.org/10.1038/nature01137

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