Abstract P142: B Cell Activating Factor Neutralization In High-Fat Diet-Induced Obese Mice Retains Adipose Tissue B Cells And Exacerbates Glucose Homeostasis

Adults with type 2 diabetes have a two-to-three-fold increased risk of cardiovascular diseases. B cell activating factor (BAFF), a tumor necrosis superfamily member, is implicated both in diabetes and cardiovascular diseases. BAFF deficiency in mice retains glucose homeostasis despite high-fat diet-induced obesity. We examined if neutralization of BAFF with an anti-BAFF antibody improves glucose utilization in high-fat diet-induced obese mice. Male C57BL/6J mice fed with a high-fat diet (60% calories from fat) for 12 weeks were segregated into two groups based on their glucose intolerance (GI) determined by a glucose tolerance test (GTT). Each group received a total of 4 injections of anti-BAFF or an isotype control antibody, and GTT was performed every two weeks. BAFF neutralization was confirmed by depletion of B2 B cells in the blood two weeks after the first anti-BAFF antibody injection. Although GI increased after continuous feeding of a high-fat diet, no differences in GI was observed between the groups till 18 weeks on diet. At 20 weeks, GI was significantly higher in the anti-BAFF treated group compared to the control group. Extensive cellular phenotyping using flow cytometry revealed that BAFF neutralization depleted mature B2 B cells in the spleen and blood but did not affect the CD4+ T cells and CD8+ T cells. No differences were found in fat accumulation in the liver, whole body fat content, visceral adipose tissue (VAT) weight, or in the number of VAT-infiltrated M1 and M2 macrophages, eosinophils, natural killer T cells, CD4+ T cells, and CD8+ T cells. Unexpectedly, in the VAT of anti-BAFF antibody-treated mice, B2 cells were retained, whereas, the number of CD4+ T cells and dead adipocytes was higher. Real-time RT-PCR analysis of stromal vascular fraction from VAT revealed increased expression of both the M1 and M2 macrophage markers IL-1β, IL-6, IL-10, Arg1, and Mrc1 in the anti-BAFF treated mice. Altogether, these results suggest BAFF neutralization promotes inflammation in the VAT of obese mice and exacerbates systemic glucose intolerance. Furthermore, our results highlight the need for more studies on the use of anti-BAFF biologics for the treatment of systemic lupus erythematosus patients who are diabetic.