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The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

Nature Medicine volume 17, pages 179188 (2011) | Download Citation

Abstract

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

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Acknowledgements

We thank Vishva M. Dixit at Genentech for providing caspase-1–specific antibody and Nlrp3−/− mice and J. Suttles from the University of Louisville for L929 media. We also thank S. Bond for expert technical assistance and D.H. Ryan, C. Bouchard and J.M. Salbaum for helpful discussions. This work was supported in part by pilot grants to B.V. and V.D.D. from the Nutrition and Obesity Research Center (US National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK072476). The research in the Dixit laboratory is supported in part by the NIH (R01AG31797), the Coypu Foundation and the Pennington Biomedical Research Foundation. K.S. was partially supported by the NIH (DK083615). This work used the facilities of the Genomics and Cell Biology & Bioimaging Core supported by NIH grant 1 P20 RR02/1945.

Author information

Affiliations

  1. Laboratory of Neuroendocrine-Immunology, Louisiana State University, Baton Rouge, Louisiana, USA.

    • Bolormaa Vandanmagsar
    • , Yun-Hee Youm
    • , Anthony Ravussin
    •  & Vishwa Deep Dixit
  2. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, USA.

    • Bolormaa Vandanmagsar
    • , Yun-Hee Youm
    • , Anthony Ravussin
    • , Jose E Galgani
    • , Krisztian Stadler
    • , Randall L Mynatt
    • , Eric Ravussin
    •  & Vishwa Deep Dixit
  3. Human Physiology Laboratory, Louisiana State University, Baton Rouge, Louisiana, USA.

    • Jose E Galgani
    •  & Eric Ravussin
  4. Oxidative Stress and Disease Laboratory, Louisiana State University, Baton Rouge, Louisiana, USA.

    • Krisztian Stadler
  5. Department of Biological Sciences, Louisiana State University System, Baton Rouge, Louisiana, USA.

    • Jacqueline M Stephens

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Contributions

B.V. performed real-time PCRs, flow cytometry assays, adipose tissue macrophage selections, some western blots, ITT, GTT and cytokine assays, managed the transgenic animal colony and participated in experimental design, data analysis and manuscript preparation. Y.-H.Y. performed all caspase-1 and IL1β western blots, adipose and liver histologies, and macrophage culture experiments and analyzed the data. A.R. Performed body composition analysis, tissue collections, lipid analysis, animal husbandry, genotyping, ITT, GTT and adipocyte size measurement. J.E.G. and E.R. designed and supervised the human studies, analyzed the glucose and insulin sensitivity data in obese T2DM subjects and discussed the hypotheses. K.S. performed the caspase-1 western blot in the kidneys of HFD fed WT and Nlrp3 null mice. R.L.M. participated in standardizing the ITT and GTT assays and advised on the design of experiments for liver fatty acid synthesis and oxidation gene expression. J.M.S. performed the western blots for some of the insulin-signaling experiments, helped with data interpretation, discussed the hypotheses and participated in manuscript preparation. V.D.D. conceived the project, designed the experiments, performed some of the cytokine assays and flow cytometry, helped with data interpretation, participated in data analysis, directed the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vishwa Deep Dixit.

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DOI

https://doi.org/10.1038/nm.2279

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