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 2

Ltb4r1KO blunts LTB4-mediated B2 cell chemotaxis both in vitro and in vivo.

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Ltb4r1KO blunts LTB4-mediated B2 cell chemotaxis both in vitro and in v...
(A) In vitro B2 cell chemotaxis in response to LTB4 treatment. (B) Effect of LTB4R1 inhibitor (100 nM) on LTB4-mediated (50 nM) B2 cell chemotaxis. (C) LTB4 concentration in VAT of LFD- and HFD-fed WT mice. (D) Schematic diagram illustrating in vivo tracking of PKH26-labeled WT and Ltb4r1KO donor B2 cells in WT recipient mice. Recruitment of CD19+PKH26+ cells into VAT (E and F) and peritoneal cavity (G and H) of WT obese and lean recipient mice. Data are presented as mean ± SEM. n = 6-8 per group (A–C); n = 6 per group (E–H). *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test (A, C, E–H); 1-way ANOVA with Bonferroni’s post test (B).