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, 64 (2), 593-603

B-1a Lymphocytes Attenuate Insulin Resistance

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B-1a Lymphocytes Attenuate Insulin Resistance

Lei Shen et al. Diabetes.

Abstract

Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell-derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell-deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell-activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell-depleting, B-1a cell-sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance.

Figures

Figure 1
Figure 1
B-1a cells play a protective role against glucose intolerance. A: Frequency of CD19+ B-cell subpopulations in the PerC (left panel), VAT (middle panel), and spleen (right panel) from C57BL/6J mice fed the NCD or HFD for 9 weeks (n = 5, representative of three experiments). B: Absolute cell counts of B-cell subpopulations of mice fed the NCD or HFD (n = 5). Body weights (C), GTT with AUC analysis (D), ITT (E), and fasting insulin levels (F) of HFD Bnull recipients, 1 week after receiving PBS, B-1a, or B-2 cells (n = 5). G: IL-10 concentration in 24-h PerC culture supernatant (n = 5). H: Serum IgM concentration (n = 5). Values are given as mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005.
Figure 2
Figure 2
IL-10 production is impaired in obese mice. AC: Frequency of GFP+ cells within each subpopulation in the PerC, VAT, and spleen from IL-10 EGFP mice fed the NCD or HFD for 9 weeks (n = 5–6, representative of three experiments). D and E: IL-10 and TNF-α concentration in 48-h PerC and VAT culture supernatants (n = 6). Body weights (F), GTT with AUC analysis (G), and fasting insulin (H) of HFD Bnull mice 1 week after receiving PBS, WT B-1a, or IL10null B-1a cells (n = 5). I: Serum IgM concentration 1 week after B-1a cell transfer (n = 5). J: TNF-α production in VAT macrophages. FACS plots are representative of two experiments. SSC-A, side scatter-area. Cytokine concentrations of IL-10 (K), TNF-α (L), and IL-6 (M) in 60-h coculture of WT PerC and VAT macrophages with WT or IL-10null B-1a cells (n = 3 per group, two replicates). Values are given as mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005; ****P < 0.0001.
Figure 3
Figure 3
Polyclonal IgM, but not monoclonal anti-PC IgM, ameliorates glucose intolerance. Body weights (A) and GTT with AUC (B) 1 week after receiving PBS, WT B-1a, sIgMnull B-1a, WT B-2, or sIgMnull B-2 cells (n = 5–8). Fasting insulin (C), IgM concentration in serum (D), and VAT lysate (E) 1 week after B-1a cell transfer (n = 4). Body weights (F), GTT with AUC (G), and fasting insulin (H) of HFD Bnull mice 1 week after receiving PBS, isotype control, polyclonal IgM, or E06 monoclonal anti-PC IgM (n = 5 for E06 treatment, n = 15 for the rest). I: Anti-PC IgM in serum from NCD and HFD mice (n = 10). J: Anti-PC IgM in serum from IR and IS obese humans (n = 32 and 30). OD, optical density. K: Cytokine concentrations in 24-h supernatants from PerC macrophages cultured with the isotype control or polyclonal IgM (n = 3). MCP-1, monocyte chemoattractant protein-1. Values are given as mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005; ****P < 0.0001.
Figure 4
Figure 4
BAFF-deficient (BAFFnull) and anti-BAFF antibody (Ab)–treated obese mice exhibit superior glucose metabolic control compared with WT and Bnull mice. Body weights (A), GTT with AUC (B), and ITT (C) of HFD WT, BAFFnull, and Bnull mice (n = 5). GTT with AUC (D), body weights (E), and fasting insulin (F) of HFD WT mice 4 weeks after they received anti-BAFF antibody or isotype control (n = 5). IgG concentration in serum (G) and VAT lysate (H) 5 weeks after anti-BAFF antibody treatment (n = 5). Cytokine concentrations in 24-h cultures of PerC (I) or spleen (J) cells stimulated with LPS from isotype control and BAFF antibody–treated mice (n = 5). K: mRNA expression in VAT from isotype control and BAFF antibody–treated mice (n = 4). Values are given as mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005.

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