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The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

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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Figure 1: Reduction of Nlrp3 and IL-1β expression is associated with improvement of insulin sensitivity.
Figure 2: Elimination of Nlrp3 expression prevents obesity-induced caspase-1 cleavage and IL-1β and IL-18 activation.
Figure 3: The Nlrp3 inflammasome regulates insulin sensitivity and steatohepatitis in obesity.
Figure 4: Nlrp3 senses ceramide to induce IL-1β and regulates adipose tissue macrophage activation in obesity.
Figure 5: Ablation of the Nlrp3 inflammasome reduces adipose tissue effector T cells without affecting Treg cells in visceral fat of obese mice.
Figure 6: Elimination of the Nlrp3 inflammasome reduces obesity-induced macrophage–mediated T cell activation in adipose tissue.

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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.

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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.

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Correspondence to Vishwa Deep Dixit.

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Vandanmagsar, B., Youm, YH., Ravussin, A. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17, 179–188 (2011). https://doi.org/10.1038/nm.2279

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