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Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance
Keiji Tanigaki, … , Philip W. Shaul, Chieko Mineo
Keiji Tanigaki, … , Philip W. Shaul, Chieko Mineo
Published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):309-322. https://doi.org/10.1172/JCI89333.
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Research Article Metabolism Vascular biology Article has an altmetric score of 56

Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance

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Abstract

Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance. Moreover, IgG transferred from patients with T2DM but not from metabolically healthy subjects caused insulin resistance in IgG-deficient mice via FcγRIIB, indicating that similar processes may be operative in T2DM in humans. Mechanistically, the activation of FcγRIIB by IgG from obese mice impaired endothelial cell insulin transcytosis in culture and in vivo. These effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM patients was also hyposialylated. In HFD-fed mice, supplementation with the sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and preserved insulin sensitivity without affecting weight gain. Thus, IgG sialylation and endothelial FcγRIIB may represent promising therapeutic targets to sever the link between obesity and T2DM.

Authors

Keiji Tanigaki, Anastasia Sacharidou, Jun Peng, Ken L. Chambliss, Ivan S. Yuhanna, Debabrata Ghosh, Mohamed Ahmed, Alexander J. Szalai, Wanpen Vongpatanasin, Robert F. Mattrey, Qiushi Chen, Parastoo Azadi, Ildiko Lingvay, Marina Botto, William L. Holland, Jennifer J. Kohler, Shashank R. Sirsi, Kenneth Hoyt, Philip W. Shaul, Chieko Mineo

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Figure 3

IgG isolated from HFD-fed WT mice induces glucose intolerance and insulin resistance in B–/– mice via endothelial FcγRIIB.

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IgG isolated from HFD-fed WT mice induces glucose intolerance and insuli...
(A) Male WT or B–/– mice were fed a control diet or a HFD for 12 weeks, and a GTT was performed. n = 7–9. *P < 0.05 versus WT control. (B and C) Male B–/– mice were fed a HFD for 12 weeks, and while continuing the HFD, they were i.p. injected with IgG (150 μg/mouse, 2 times/week) isolated from WT mice fed either a control diet (Con-IgG) or a HFD (HFD-IgG). GTTs (B) and ITTs (C) were performed after 1 week and 2 weeks of IgG administration, respectively. (B and C) n = 6–7. *P < 0.05 versus Con-IgG. (D and E) Using the study design and readouts described for B and C, IgG transfer experiments were performed in male B–/– mice given IgG isolated from FcγRIIB–/– mice fed either a control diet or a HFD. Endpoints were the GTT (D) and ITT (E). (D and E) n = 6–7. *P < 0.05 versus IgG from FcγRIIB–/– control mice. (F and G) IgG transfer studies were performed in male B–/– versus B–/– FcγRIIB–/– mice administered IgG isolated from HFD-fed WT mice. GTTs (F) and ITTs (G) were performed. (F and G) n = 7–8. *P < 0.05 versus B–/– mice. (H and I) IgG transfer experiments were performed in male B–/– FcγRIIBfl/fl and B–/– FcγRIIBΔEC mice administered IgG isolated from HFD-fed WT mice. GTTs (H) and ITTs (I) were performed. (H and I) n = 11–14. *P < 0.05 versus B–/– FcγRIIBfl/fl mice. Values represent the mean ± SEM. P values were determined by 2-way ANOVA with Tukey’s post-hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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