B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.
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.
Winer, DA; Winer, S; Shen, L; Wadia, PP; Yantha, J; Paltser, G; Tsui, H; Wu, P; Davidson, MG; Alonso, MN; Leong, HX; Glassford, A; Caimol, M; Kenkel, JA; Tedder, TF; McLaughlin, T; Miklos, DB; Dosch, H-M; Engleman, EG
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