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
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).
Gregor, M.F. & Hotamisligil, G.S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
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).
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).
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).
Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).
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).
Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).
Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).
Pham, C.T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006).
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).
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).
Rensen, S.S. et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am. J. Pathol. 175, 1473–1482 (2009).
Houghton, A.M. et al. Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010).
Houghton, A.M. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 9, 1732–1737 (2010).
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).
Devaney, J.M. et al. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 544, 129–132 (2003).
Brightbill, H.D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).
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).
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).
Li, P. et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010).
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).
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).
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
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 (PDF 917 kb)
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2885
This article is cited by
-
Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network
Cardiovascular Diabetology (2024)
-
Elevated first-trimester neutrophil elastase and proteinase 3 increase the risk of gestational diabetes mellitus and adverse fetal outcomes
Reproductive Biology and Endocrinology (2024)
-
Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages
Nature Communications (2024)
-
Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice
Nature Communications (2024)
-
Sialic acids cleavage induced by elastin-derived peptides impairs the interaction between insulin and its receptor in adipocytes 3T3-L1
Journal of Physiology and Biochemistry (2024)