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

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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.


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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.).

Author information




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).

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