B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies

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Abstract

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell–depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

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Figure 1: B cell and antibody profile in DIO mice.
Figure 2: B cell deficiency modulates glucose metabolism in DIO mice.
Figure 3: B cells influence VAT T cell and macrophage function.
Figure 4: HFD IgG induces abnormal glucose metabolism in recipient Bnull mice.
Figure 5: A CD20-specific B cell-depleting antibody improves obesity-induced glucose abnormalities.

Change history

  • 06 June 2011

     In the version of this article initially published, the authors did not acknowledge Canadian Institutes of Health Research grant 111156 (H.M.D.), which also supported the study. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Franks, P.W. et al. Childhood obesity, other cardiovascular risk factors and premature death. N. Engl. J. Med. 362, 485–493 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Olefsky, J.M. & Glass, C.K. Macrophages, inflammation and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    CAS  Article  Google Scholar 

  3. 3

    Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Lumeng, C.N., Deyoung, S.M., Bodzin, J.L. & Saltiel, A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56, 16–23 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Rocha, V.Z. et al. Interferon-γ, a TH1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103, 467–476 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    Ilan, Y. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl. Acad. Sci. USA 107, 9765–9770 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836–1845 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Duffaut, C., Galitzky, J., Lafontan, M. & Bouloumie, A. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem. Biophys. Res. Commun. 384, 482–485 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Jagannathan, M. et al. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 53, 1461–1471 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Caspar-Bauguil, S. et al. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett. 579, 3487–3492 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Martin, R.M., Brady, J.L. & Lew, A.M. The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice. J. Immunol. Methods 212, 187–192 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Strissel, K.J. et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56, 2910–2918 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K.A. B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423–426 (1991).

    CAS  Article  Google Scholar 

  22. 22

    Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    CAS  Article  Google Scholar 

  23. 23

    Cintra, D.E. et al. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J. Hepatol. 48, 628–637 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Steppan, C.M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Ma, L.J. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53, 336–346 (2004).

    CAS  Article  Google Scholar 

  26. 26

    LeBien, T.W. & Tedder, T.F. B lymphocytes: how they develop and function. Blood 112, 1570–1580 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Nimmerjahn, F. & Ravetch, J.V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Bouaziz, J.D. et al. Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc. Natl. Acad. Sci. USA 104, 20878–20883 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Matsushita, T., Yanaba, K., Bouaziz, J.D., Fujimoto, M. & Tedder, T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118, 3420–3430 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    DiLillo, D.J., Yanaba, K. & Tedder, T.F. B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J. Immunol. 184, 4006–4016 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Falorni, A. et al. Autoantibody recognition of COOH-terminal epitopes of GAD65 marks the risk for insulin requirement in adult-onset diabetes mellitus. J. Clin. Endocrinol. Metab. 85, 309–316 (2000).

    CAS  PubMed  Google Scholar 

  32. 32

    Zimering, M.B. & Pan, Z. Autoantibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells. J. Clin. Endocrinol. Metab. 94, 2171–2177 (2009).

    CAS  Article  Google Scholar 

  33. 33

    Gómez-Touriño, I. et al. Autoantibodies to glial fibrillary acid protein and S100beta in diabetic patients. Diabet. Med. 27, 246–248 (2010).

    Article  Google Scholar 

  34. 34

    Alkhouri, N. et al. Adipocyte apoptosis, a link between obesity, insulin resistance and hepatic steatosis. J. Biol. Chem. 285, 3428–3438 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Wueest, S. et al. Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J. Clin. Invest. 120, 191–202 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Mamane, Y. et al. The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation. Diabetes 58, 2006–2017 (2009).

    CAS  Article  Google Scholar 

  37. 37

    Hay, J.C., Chao, D.S., Kuo, C.S. & Scheller, R.H. Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells. Cell 89, 149–158 (1997).

    CAS  Article  Google Scholar 

  38. 38

    Hotamisligil, G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).

    CAS  Article  Google Scholar 

  39. 39

    Yanaba, K. et al. B-lymphocyte contributions to human autoimmune disease. Immunol. Rev. 223, 284–299 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Ait-Oufella, H. et al. B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207, 1579–1587 (2010).

    CAS  Article  Google Scholar 

  41. 41

    DiLillo, D.J. et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180, 361–371 (2008).

    CAS  Article  Google Scholar 

  42. 42

    Hussain, B.M., Geetha, N., Lali, V. & Pandey, M. Rituximab induced hypoglycemia in non-Hodgkin's lymphoma. World J. Surg. Oncol. 4, 89 (2006).

    Article  Google Scholar 

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Acknowledgements

We thank D. Jones for secretarial assistance; C. Benike for critical review of the manuscript; A. Chawla for critical review of the figures; C. Wang, L. Tolentino and K. Heydari for assistance with flow cytometry; and Y. Yang and L. Herzenberg for help in developing macrophage and B cell subset gates. These studies were supported by US National Institutes of Health grants CA141468 and DK082537 (E.G.E) and Canadian Institutes of Health Research Grant 111156 (H.M.D.).

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D.A.W. and S.W. conceived the study, did experimental work and wrote the manuscript. L.S. was involved in experimental work, project planning and manuscript preparation. P.P.W., A.G., T.M. and D.B.M. contributed the human array data. J.Y., G.P., M.G.D., M.N.A., H.T., P.W., H.X.L., J.A.K. and M.C. did experimental work; T.F.T. contributed the CD20-specific mAb and was involved in manuscript preparation. H.M.D. supervised parts of the project and was involved in manuscript preparation; E.G.E. was involved in project planning, financing, supervision, data analysis and manuscript preparation. E.G.E. and H.M.D. are both senior authors.

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Correspondence to Daniel A Winer or Edgar G Engleman.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Methods (PDF 4883 kb)

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Winer, D., Winer, S., Shen, L. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17, 610–617 (2011). https://doi.org/10.1038/nm.2353

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