[go: up one dir, main page]
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.

  • Letter
  • Published:

Protection from obesity-induced insulin resistance in mice lacking TNF-α function

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

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Growth curves and adiposity of TNF-α−/−and TNF-α+/+mice.
Figure 2: Measures of glucose homeostasis in TNF-α−/−and TNF-α+/+mice.
Figure 3: Measures of glucose homeostasis in ob/ob and ob/ob p55−/−p75−/−mice.
Figure 4: Circulating free fatty-acid levels in TNF-α−/−and TNF-α+/+mice.
Figure 5: The levels of Glut4 protein in TNF-α−/−and TNF-α+/+mice.
Figure 6: Levels of insulin-stimulated tyrosine phosphorylation of insulin receptor in fat, muscle and liver tissues of TNF-α−/−and TNF-α+/+mice.

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah M. Wiesbrock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W. Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gkhan S. Hotamisligil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gkhan S. Hotamisligil.

Rights and permissions

Reprints 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

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/39335

This article is cited by

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