Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase (original) (raw)

Nature Medicine volume 18, pages 1407–1412 (2012)Cite this article

Subjects

Abstract

Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes1,2. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process3,4,5,6,7,8. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells9,10,11. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models12. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 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. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).
    Article CAS Google Scholar
  2. Gregor, M.F. & Hotamisligil, G.S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).
    Article CAS Google Scholar
  3. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
    Article CAS Google Scholar
  4. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
    Article CAS Google Scholar
  5. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).
    Article CAS Google Scholar
  6. Winer, D.A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).
    Article CAS Google Scholar
  7. Liu, J. et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15, 940–945 (2009).
    Article CAS Google Scholar
  8. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).
    Article CAS Google Scholar
  9. Mantovani, A., Cassatella, M.A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011).
    Article CAS Google Scholar
  10. Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).
    Article CAS Google Scholar
  11. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).
    Article CAS Google Scholar
  12. Pham, C.T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006).
    Article CAS Google Scholar
  13. Elgazar-Carmon, V., Rudich, A., Hadad, N. & Levy, R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894–1903 (2008).
    Article CAS Google Scholar
  14. Macdonald, S.J. et al. The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase–—GW311616A a development candidate. Bioorg. Med. Chem. Lett. 11, 895–898 (2001).
    Article CAS Google Scholar
  15. Rensen, S.S. et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am. J. Pathol. 175, 1473–1482 (2009).
    Article CAS Google Scholar
  16. Houghton, A.M. et al. Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010).
    Article CAS Google Scholar
  17. Houghton, A.M. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 9, 1732–1737 (2010).
    Article CAS Google Scholar
  18. Walsh, D.E. et al. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J. Biol. Chem. 276, 35494–35499 (2001).
    Article CAS Google Scholar
  19. Devaney, J.M. et al. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 544, 129–132 (2003).
    Article CAS Google Scholar
  20. Brightbill, H.D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).
    Article CAS Google Scholar
  21. Oh, D.Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).
    Article CAS Google Scholar
  22. Lu, M. et al. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat. Med. 17, 618–622 (2011).
    Article CAS Google Scholar
  23. Li, P. et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010).
    Article CAS Google Scholar
  24. Talukdar, S. & Hillgartner, F.B. The mechanism mediating the activation of acetyl–coenzyme A carboxylaseα gene transcription by the liver X receptor agonist T0-901317. J. Lipid Res. 47, 2451–2461 (2006).
    Article CAS Google Scholar
  25. Kalupov, T. et al. Structural characterization of mouse neutrophil serine proteases and identification of their substrate specificities: relevance to mouse models of human inflammatory diseases. J. Biol. Chem. 284, 34084–34091 (2009).
    Article CAS Google Scholar

Download references

Acknowledgements

This work was supported by grants to J.M.O. from the US National Institutes of Health (NIH): DK033651, DK074868, T32 DK 007494, DK 090962 and DK063491. This work was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH through cooperative agreement U54 HD 012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research. We wish to thank S. Shapiro (University of Pittsburgh) for helpful comments over the course of the project, C. Pham (Washington University, St. Louis) for providing cathepsin G and neutrophil elastase double knockout mice, S. Nalbandian at University of California San Diego for breeding and caring for the NEKO mice and P. Bansal (Pfizer), B. Ghosh (Pfizer) and J. Wellen (Pfizer) for the neutrophil elastase activity imaging studies.

Author information

Author notes

  1. Saswata Talukdar
    Present address: Present address: Pfizer, CVMED–Diabetes Prevention and Remission, Cambridge, Massachusetts, USA.,
  2. Saswata Talukdar and Da Young Oh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, La Jolla, California, USA
    Saswata Talukdar, Da Young Oh, Gautam Bandyopadhyay, Jianfeng Xu, Joanne McNelis, Min Lu, Pingping Li, Jachelle Ofrecio, Michael Lin & Jerrold M Olefsky
  2. Pfizer, Cardiovascular, Metabolic and Endocrine Diseases (CVMED)–Diabetes Prevention and Remission, Cambridge, Massachusetts, USA
    Dongmei Li, Qingyun Yan, Yimin Zhu & Martin B Brenner

Authors

  1. Saswata Talukdar
  2. Da Young Oh
  3. Gautam Bandyopadhyay
  4. Dongmei Li
  5. Jianfeng Xu
  6. Joanne McNelis
  7. Min Lu
  8. Pingping Li
  9. Qingyun Yan
  10. Yimin Zhu
  11. Jachelle Ofrecio
  12. Michael Lin
  13. Martin B Brenner
  14. Jerrold M Olefsky

Contributions

S.T. and D.Y.O. designed and performed the experiments. S.T., D.Y.O. and J.M.O. analyzed and interpreted data and co-wrote the manuscript. All other authors performed experiments and contributed to discussions. This work was supported by grants to J.M.O., as detailed above.

Corresponding author

Correspondence toJerrold M Olefsky.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Talukdar, S., Oh, D., Bandyopadhyay, G. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase.Nat Med 18, 1407–1412 (2012). https://doi.org/10.1038/nm.2885

Download citation

This article is cited by