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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

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 7

ManNAc treatment protects mice from obesity-induced glucose intolerance and insulin resistance.

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ManNAc treatment protects mice from obesity-induced glucose intolerance ...
(A) Male WT mice were fed a HFD and either regular drinking water (control) or ManNAc-supplemented drinking water for 6 weeks. Plasma IgG was isolated, and its sialylation was evaluated by SNA-lectin blotting. Graph depicts the relative sialylation. n = 5. (B) BW and (C) fasting plasma glucose levels were measured, and (D) a GTT was performed. (E) Mice were continued on the HFD, and an ITT was performed 1 week later. n = 9. (A–E) Values represent the mean ± SEM. (A–C) *P < 0.05 and ****P < 0.001, by Student’s t test; (D and E) *P < 0.05, ManNAc versus control, by 2-way ANOVA with Tukey’s post-hoc test.
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