Edgar Engleman and his colleagues show that B cell production of pathogenic IgG antibodies is involved in obesity-induced insulin resistance. They also show that B cell depletion in obese mice ameliorates metabolic disease, and that obese, insulin-resistant humans have a unique profile of IgG autoantibodies. These results suggest a possible new therapeutic target to treat insulin resistance. 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.

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