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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Cancer and Metastasis Reviews Open Access 23 July 2022
Microbiome Open Access 04 April 2022
Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance
Molecular Psychiatry Open Access 01 April 2022
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Franks, P.W. et al. Childhood obesity, other cardiovascular risk factors and premature death. N. Engl. J. Med. 362, 485–493 (2010).
Olefsky, J.M. & Glass, C.K. Macrophages, inflammation and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).
Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).
Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
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).
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).
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).
Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).
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).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
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).
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).
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).
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).
Jagannathan, M. et al. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 53, 1461–1471 (2010).
Caspar-Bauguil, S. et al. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett. 579, 3487–3492 (2005).
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).
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).
Strissel, K.J. et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56, 2910–2918 (2007).
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).
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).
Cintra, D.E. et al. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J. Hepatol. 48, 628–637 (2008).
Steppan, C.M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).
Ma, L.J. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53, 336–346 (2004).
LeBien, T.W. & Tedder, T.F. B lymphocytes: how they develop and function. Blood 112, 1570–1580 (2008).
Nimmerjahn, F. & Ravetch, J.V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).
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).
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).
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).
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).
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).
Gómez-Touriño, I. et al. Autoantibodies to glial fibrillary acid protein and S100beta in diabetic patients. Diabet. Med. 27, 246–248 (2010).
Alkhouri, N. et al. Adipocyte apoptosis, a link between obesity, insulin resistance and hepatic steatosis. J. Biol. Chem. 285, 3428–3438 (2010).
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).
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).
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).
Hotamisligil, G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).
Yanaba, K. et al. B-lymphocyte contributions to human autoimmune disease. Immunol. Rev. 223, 284–299 (2008).
Ait-Oufella, H. et al. B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207, 1579–1587 (2010).
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).
Hussain, B.M., Geetha, N., Lali, V. & Pandey, M. Rituximab induced hypoglycemia in non-Hodgkin's lymphoma. World J. Surg. Oncol. 4, 89 (2006).
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.
About this article
Cite this article
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
Gut microbiota–derived metabolite 3-idoleacetic acid together with LPS induces IL-35+ B cell generation
Journal of Biomedical Science (2022)
Nature Reviews Immunology (2022)
Cellular & Molecular Immunology (2022)