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

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 6

Hyposialylated IgG2c from HFD-fed mice blunts endothelial insulin transcytosis and invokes insulin resistance via FcγRIIB, and IgG from T2DM subjects is similarly hyposialylated.

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Hyposialylated IgG2c from HFD-fed mice blunts endothelial insulin transc...
(A–C) The effects of the IgG subclasses IgG1 (A), IgG2b (B), or IgG2c (C) (10 μg/ml) from control diet– or HFD-fed WT mice on eNOS activation by insulin (100 nM) were assessed in cultured endothelial cells. (A–C) n = 6–11. (D) Sialylation of IgG2c (Sial-IgG2c) from control diet– or HFD-fed mice was evaluated by SNA-lectin blotting. n = 6. (E) Sialylation of IgG isolated from nondiabetic humans and T2DM patients was evaluated by SNA-lectin blotting. n = 6. (F) IgG2c from control diet– or HFD-fed mice was treated with vehicle (Con) or NA, and sialylation was evaluated by SNA-lectin blotting. n = 3. (G) Endothelial cells were preincubated with Con-IgG2c or HFD-IgG2c treated with vehicle or NA, and eNOS activation by insulin was assessed. n = 6. (H) Confluent endothelial cells on Transwells were preincubated with Con-IgG2c or HFD-IgG2c treated with vehicle or NA, and insulin transcytosis was assessed in the absence or presence of the NO donor SNAP (100 nM), control antibody (C, 10 μg/ml), or FcγRIIB-blocking antibody (BL, 10 μg/ml). n = 7. (I–K) B–/– mice were fed a HFD for 12 weeks and injected with Con-IgG that was treated ex vivo with vehicle (Con-IgG) or NA (NA-IgG). Fasting plasma glucose was measured before and after 1 week of injections (I), and then GTTs (J) and ITTs (K) were performed. (I–K) n = 7–16. *P < 0.05, NA versus Con-IgG. (L and M) Using the same study design as in I–K, IgG transfer experiments were performed in B–/– and B–/– FcγRIIB–/– mice administered Con-IgG or NA-IgG. GTTs (L) and ITTs (M) were performed. (L and M) n = 5–6. *P < 0.05, B–/– NA-IgG versus B–/– Con-IgG; †P < 0.05, B–/– FcγRIIB–/– versus B–/–. (N) The Fc Asn297–associated glycan structure was evaluated by glycoproteomic analysis using pooled mouse Con-IgG2c and HFD-IgG2c. Values represent the mean ± SEM (A–M). *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001, by 1-way ANOVA with Tukey’s post-hoc test (A–C and F–I), Student’s t test (D and E), and 2-way ANOVA (J–M).