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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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.).
The authors declare no competing financial interests.
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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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