Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance
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
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
View: Text | PDF
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

×

Figure 4

IgG isolated from human T2DM patients induces glucose intolerance and insulin resistance in B–/– mice via FcγRIIB.

Options: View larger image (or click on image) Download as PowerPoint
IgG isolated from human T2DM patients induces glucose intolerance and in...
(A–D) 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 non-T2DM control subjects versus IgG from T2DM subjects. After 1 week of injections, (A) BW was measured, (B) plasma glucose was measured after a 4- to 6-hour fast, and (C) a GTT was performed. (D) An ITT was performed following a second week of IgG injections. (A–D) n = 6 IgG samples, each evaluated in 3 to 5 mice. (C and D) *P < 0.05 versus Con-IgG. (E–G) Using the study design described for A–D, IgG transfer experiments were performed by administering human T2DM-IgG to male B–/– mice and B–/– FcγRIIB–/– mice. (E) Fasting plasma glucose levels were measured before IgG injection and at 1 week. n = 3 IgG samples. (F) A GTT was performed after 1 week of injections, and (G) an ITT was performed after 2 weeks of injections. (F and G) n = 3 IgG samples. *P < 0.05 versus B–/–. Values represent the mean ± SEM. *P < 0.05, ***P < 0.005, ****P < 0.001, by Student’s t test (A and B, with significance found in B), 1-way ANOVA with Tukey’s post-hoc test (E), and 2-way ANOVA with Tukey’s post-hoc test (C, D, F, and G).