Protection from obesity-induced insulin resistance in mice lacking TNF-α function (original) (raw)

Nature volume 389, pages 610–614 (1997) Cite this article

Abstract

Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus1,2,3. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-α is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans4,5,6,7,8,9,10 and it blocks the action of insulin in cultured cells and whole animals10,11,12,13,14. To investigate the role of TNF-α in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-α and those encoding the two receptors for TNF-α. The absence of TNF-α resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFα-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-α is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.

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

Access options

Subscribe to this journal

Receive 52 print issues and online access

$199.00 per year

only $3.83 per issue

Buy this article

USD 39.95

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

Additional access options:

Similar content being viewed by others

References

  1. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 45, 3–10 (1997).
    Article Google Scholar
  2. Carey, V. J. et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women – the nurses health study. Am. J. Epidemiol. 145, 614–619 (1997).
    Article CAS PubMed Google Scholar
  3. Edelstein, S. L. et al. Predictors of progression from impaired glucose tolerance to NIDDM. Diabetes 46, 701–710 (1997).
    Article CAS PubMed Google Scholar
  4. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
    Article ADS CAS PubMed Google Scholar
  5. Hofmann, C. et al. Altered gene expression for tumor necrosis factor-α and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134, 264–270 (1994).
    Article CAS PubMed Google Scholar
  6. Hamann, A. et al. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat. Diabetes 44, 1266–1273 (1995).
    Article CAS PubMed Google Scholar
  7. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).
    Article CAS PubMed PubMed Central Google Scholar
  8. Kern, P. A. et al. The expresison of tumor necrosis factor in adipose tissue: regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95, 2111–2119 (1995).
    Article CAS PubMed PubMed Central Google Scholar
  9. Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R. & Kern, P. A. The expression of TNFα by human muscle: relationship to insulin resistance. J. Clin. Invest. 97, 1111–1116 (1996).
    Article CAS PubMed PubMed Central Google Scholar
  10. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Differential regulation of the p80 TNF receptor in human obesity and insulin resistance. Diabetes 46, 451–455 (1997).
    Article CAS PubMed Google Scholar
  11. Feinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B. & Karasik, A. Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J. Biol. Chem. 268, 26055–26058 (1993).
    CAS PubMed Google Scholar
  12. Hotamisligil, G. S., Murray, D. L., Choy, L. N. & Spiegelman, B. M. TNF-α inhibits signaling from insulin receptor. Proc. Natl Acad. Sci. USA 91, 4854–4858 (1994).
    Article ADS CAS PubMed PubMed Central Google Scholar
  13. Kanety, H., Feinstein, R., Papa, M. Z., Hemi, R. & Karasik, A. Tumor necrosis factor-α-induced phosphorylation of insulin receptor substrate-1 (IRS-1). J. Biol. Chem. 270, 23780–23784 (1995).
    Article CAS PubMed Google Scholar
  14. Kroder, G. et al. Tumor necrosis factor-α- and hyperglycemia-induced insulin resistance: evidence for different mechanisms and different effects on insulin signaling. J. Clin. Invest. 97, 1471–1477 (1996).
    Article CAS PubMed PubMed Central Google Scholar
  15. Hotamisligil, G. S. 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
  16. Stephens, J. M. & Pekala, P. H. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J. Biol. Chem. 266, 21839–21845 (1991).
    CAS PubMed Google Scholar
  17. Stephens, J. M., Lee, J. L. & Pilch, P. F. Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and glut4 expression without a loss of insulin receptor-mediated signal transduction. J. Biol. Chem. 272, 971–976 (1997).
    Article CAS PubMed Google Scholar
  18. Marino, M. W. et al. Characterization of tumor necrosis factor deficient mice. Proc. Natl Acad. Sci. USA 94, 8093–8098 (1997).
    Article ADS CAS PubMed PubMed Central Google Scholar
  19. Bruce, A. J. et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med. 2, 788–794 (1996).
    Article ADS CAS PubMed Google Scholar
  20. Coleman, D. L. in The Mouse in Biomedical Research (ed. Foster, M.) 125–132 (Academic, London, (1982)).
    Google Scholar
  21. Olefsky, J. M. & Molina, J. M. in Diabetes Mellitus (eds Rifkin, H. & Porte, D. J.) 121–153 (Elsevier, New York, (1990)).
    Google Scholar
  22. Cornelius, P., Lee, M. D., Marlowe, M. & Pekala, P. H. Monokine regulation of glucose transporter mRNA in L6 myotubes. Biochem. Biophys. Res. Commun. 165, 429–436 (1989).
    Article CAS PubMed Google Scholar
  23. Hotamisligil, G. S., Budavari, A., Murray, D. L. & Spiegelman, B. M. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes: central role of tumor necrosis factor-α. J. Clin. Invest. 94, 1543–1549 (1994).
    Article CAS PubMed PubMed Central Google Scholar
  24. White, M. F. & Kahn, C. R. The insulin signaling system. J. Biol. Chem. 269, 1–4 (1994).
    CAS PubMed Google Scholar
  25. Fiedorek, F. T. in Diabetes Mellitus: a Fundamental and Clinical Text (eds LeRoith, D., Taylor, S. I. & Olefsky, J. M.) 604–618 (Lippincott-Raven, Philadelphia, (1996)).
    Google Scholar
  26. Hotamisligil, G. S. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 1377–1379 (1996).
    Article ADS CAS PubMed Google Scholar

Download references

Acknowledgements

We thank J. Perschon for generation of the TNF receptor-deficient mice, and members of the Hotamisligil laboratory for discussions and support. This work is in part supported by grants from the NIH and American Diabetes Foundation (G.S.H.).

Author information

Author notes

  1. K. Teoman Uysal, Sarah M. Wiesbrock and Michael W. Marino: These authors contributed equally to this study.

Authors and Affiliations

  1. Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, USA
    K. Teoman Uysal, Sarah M. Wiesbrock & Gkhan S. Hotamisligil
  2. Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA
    Michael W. Marino

Authors

  1. K. Teoman Uysal
  2. Sarah M. Wiesbrock
  3. Michael W. Marino
  4. Gkhan S. Hotamisligil

Corresponding author

Correspondence toGkhan S. Hotamisligil.

Rights and permissions

About this article

Cite this article

Uysal, K., Wiesbrock, S., Marino, M. et al. Protection from obesity-induced insulin resistance in mice lacking TNF-α function.Nature 389, 610–614 (1997). https://doi.org/10.1038/39335

Download citation