Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling
Wei Ying, … , Olivia Osborn, Jerrold M. Olefsky
Wei Ying, … , Olivia Osborn, Jerrold M. Olefsky
Published February 13, 2017
Citation Information: J Clin Invest. 2017;127(3):1019-1030. https://doi.org/10.1172/JCI90350.
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Research Article Immunology Metabolism

Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling

Abstract

Tissue inflammation is a key component of obesity-induced insulin resistance, with a variety of immune cell types accumulating in adipose tissue. Here, we have demonstrated increased numbers of B2 lymphocytes in obese adipose tissue and have shown that high-fat diet–induced (HFD-induced) insulin resistance is mitigated in B cell-deficient (Bnull) mice. Adoptive transfer of adipose tissue B2 cells (ATB2) from wild-type HFD donor mice into HFD Bnull recipients completely restored the effect of HFD to induce insulin resistance. Recruitment and activation of ATB2 cells was mediated by signaling through the chemokine leukotriene B4 (LTB4) and its receptor LTB4R1. Furthermore, the adverse effects of ATB2 cells on glucose homeostasis were partially dependent upon T cells and macrophages. These results demonstrate the importance of ATB2 cells in obesity-induced insulin resistance and suggest that inhibition of the LTB4/LTB4R1 axis might be a useful approach for developing insulin-sensitizing therapeutics.

Authors

Wei Ying, Joshua Wollam, Jachelle M. Ofrecio, Gautam Bandyopadhyay, Dalila El Ouarrat, Yun Sok Lee, Da Young Oh, Pingping Li, Olivia Osborn, Jerrold M. Olefsky

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Figure 4

B2 cell–mediated tissue inflammation and insulin resistance in obese mice are dependent upon LTB4rR1.

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B2 cell–mediated tissue inflammation and insulin resistance in obese mic...
(A and B) GTTs and ITTs of HFD-fed Bnull mice after adoptive transfer of ATB2 cells. (C and D) The level of proinflammatory cytokines Il1b, Il6, and Tnfa in VAT and plasma of obese Bnull recipient mice after ATB2 cell transference. (E and F) The activation of NF-κb and Akt signaling pathway in VAT of HFD Bnull mice after injection of ATB2 cells. (G) The engraftment of donor B2 cells in VAT of HFD Bnull recipient mice. Two weeks after ATB2 cell transfer, the populations of CD4+ T cell subsets (Th1: IFN-γ+CD4+, Th2: Il4+CD4+, and Treg: Foxp3+CD4+, H), IFN-γ+CD8+ T cells (I), and macrophage subtypes (M1: F4/80+CD11b+CD11c+CD206–, M2: F4/80+CD11b+CD11c–CD206+, J) were measured in the VAT of HFD Bnull recipient mice. In A and B, please note that the GTT and ITT results for the HFD Bnull mice are the same as in Figure 1 and are shown again here only for comparative purposes. Data are presented as mean ± SEM. n = 6 for HFD Bnull group; n = 10 for the other groups (A and B); n = 6 per group (C–J). *P < 0.05; **P < 0.01, 1-way ANOVA with Bonferroni’s post test. ATM, adipose tissue macrophage.