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B-1a lymphocytes attenuate insulin resistance.

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.

SUBMITTER: Shen L

PROVIDER: S-EPMC4303967 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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B-1a lymphocytes attenuate insulin resistance.

Shen Lei L Chng Melissa Hui Yen MH Alonso Michael N MN Yuan Robert R Winer Daniel A DA Engleman Edgar G EG

Diabetes 20140923 2

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 obes ...[more]

PMID: 25249575

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Project description:The association of Alzheimer disease (AD) and Diabetes (DM) is less clear. Accumulation of beta amyloid (Aβ) and presence of hyperphosphorylated tau (p-tau) are hallmarks of AD, spreading in the region where insulin receptors are also found. Aβ exerts neuron toxicity, and could disturb insulin signaling of phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase (GSK)-3β and AMP-activated protein kinase (AMPK), but increase IRS-1-Ser307 phosphorylation which is viewed as insulin resistance marker. Previously we reported dipeptidyl peptidase-4 (DPP-4) mediate insulin resistance signals, and Abelmoschus esculentus (AE) subfractions F1 (rich in quercetin glucosides and triterpene ester) and F2 (containing large amount of polysaccharides) attenuate DPP-4-mediated apoptosis. In the present study, we aim to investigate if Aβ induce neuron death by regulating DPP-4 and insulin resistance signals, and the putative effect of F1 and F2. By MTT, microscopy, and Western blotting, we demonstrate treatment of appropriate doses of AE subfractions prevent Aβ-induced neuron apoptosis. F1 attenuate Aβ-induced caspase 3 expression especially at 25 μg/mL, while F2 attenuate caspase 3 activation even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced DPP-4, but increase Aβ-reduced p-AMPK and p-PI3K. The activity analysis reveals that F2 is more valid than F1 to reduce DPP-4 activity. The inhibition of DPP-4 demonstrates it plays the pivotal role in Aβ-induced neuron apoptosis. Moreover, although both F1 and F2 are effective to inhibit p-IRS-1-Ser307, F2 takes advantage to reduce p-Tau while F1 is superior to enhance p-GSK-3β. This implies AE subfractions act on different targets, and could be developed respectively. In conclusion, we demonstrate AE is potential to prevent Aβ-induced neuron damage by regulating DPP-4 and the insulin resistance cascades. AE could be an adjuvant to protect neuron degenerative disease related to Aβ and insulin resistance.

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B-1a lymphocytes attenuate insulin resistance.

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B-1a lymphocytes attenuate insulin resistance.

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