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Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

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.

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Figure 1: Neutrophils infiltrate eWAT in mice on HFD, and ablation of neutrophil elastase improves insulin sensitivity in DIO mice.
Figure 2: A high degree of insulin sensitivity in NEKO mice.
Figure 3: Neutrophils infiltrate the liver in HFD-fed mice and cause impaired insulin signaling by degradation of Irs1.
Figure 4: NEKO mice have low inflammatory tone.

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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.

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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.

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Correspondence to Jerrold M Olefsky.

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The authors declare no competing financial interests.

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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

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