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 2

Mice with endothelium-specific deletion of FcγRIIB (FcγRIIBΔEC) are protected from obesity-induced glucose intolerance and insulin resistance due to the preservation of skeletal muscle insulin delivery, insulin action, and glucose uptake.

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Mice with endothelium-specific deletion of FcγRIIB (FcγRIIBΔEC) are prot...
(A–C) Male FcγRIIBfl/fl and FcγRIIBΔEC mice were fed a control diet or a HFD for 12 weeks, and BW (A) and fat and lean mass (B and C) were evaluated. n = 5–13 (A–C). Fasting blood glucose (D) and insulin (E) levels were measured (n = 8–16), and a GTT (F; right panel shows the AUC) was performed. An ITT (G; right panel shows the AUC) and a PTT (H) were then performed, each following a 1-week recovery while mice continued the assigned diets. (F–H) n = 6–13. (I) In separate mice, following 12 weeks on a HFD, a hyperinsulinemic-euglycemic clamp was performed, and the GIR was calculated. n = 11–14. (J) One week after the PTT, the mice in A–H were fasted, and [3H]-2-deoxyglucose uptake in skeletal muscle was measured. n = 7–8. (F–H) *P < 0.05 versus FcγRIIB+/+ control diet; †P < 0.05 versus FcγRIIB+/+ HFD. (K and L) Following 12 weeks on a control diet or a HFD, mice were fasted and i.v. injected with PBS (Veh) or insulin (Ins) (1 unit/kg BW), and 5 minutes later, skeletal muscle was harvested, the phosphorylation of Akt (Ser473) was assessed by immunoblotting (K), and muscle insulin content was measured by ELISA (L). (K and L) n = 4–6. Values represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001, by 1-way ANOVA with Tukey’s post-hoc test (A–E, and I–L), 2-way ANOVA with Tukey’s post-hoc test (F–H), and Student’s t test (I).