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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)309-322
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number1
DOIs
StatePublished - Jan 2 2018

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IgG Receptors
Insulin Resistance
Obesity
Immunoglobulin G
Type 2 Diabetes Mellitus
High Fat Diet
Endothelium
Insulin
Transcytosis
Obese Mice
N-Acetylneuraminic Acid
Weight Gain
Polysaccharides
Healthy Volunteers
Skeletal Muscle
Endothelial Cells
Maintenance
Ligands

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance. / Tanigaki, Keiji; Sacharidou, Anastasia; Peng, Jun; Chambliss, Ken L.; Yuhanna, Ivan S.; Ghosh, Debabrata; Ahmed, Mohamed; Szalai, Alexander J.; Vongpatanasin, Wanpen; Mattrey, Robert F.; Chen, Qiushi; Azadi, Parastoo; Lingvay, Ildiko; Botto, Marina; Holland, William L.; Kohler, Jennifer J.; Sirsi, Shashank R.; Hoyt, Kenneth; Shaul, Philip W.; Mineo, Chieko.

In: Journal of Clinical Investigation, Vol. 128, No. 1, 02.01.2018, p. 309-322.

Research output: Contribution to journalArticle

Tanigaki, K, Sacharidou, A, Peng, J, Chambliss, KL, Yuhanna, IS, Ghosh, D, Ahmed, M, Szalai, AJ, Vongpatanasin, W, Mattrey, RF, Chen, Q, Azadi, P, Lingvay, I, Botto, M, Holland, WL, Kohler, JJ, Sirsi, SR, Hoyt, K, Shaul, PW & Mineo, C 2018, 'Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance', Journal of Clinical Investigation, vol. 128, no. 1, pp. 309-322. https://doi.org/10.1172/JCI89333
Tanigaki, Keiji ; Sacharidou, Anastasia ; Peng, Jun ; Chambliss, Ken L. ; Yuhanna, Ivan S. ; Ghosh, Debabrata ; Ahmed, Mohamed ; Szalai, Alexander J. ; Vongpatanasin, Wanpen ; Mattrey, Robert F. ; Chen, Qiushi ; Azadi, Parastoo ; Lingvay, Ildiko ; Botto, Marina ; Holland, William L. ; Kohler, Jennifer J. ; Sirsi, Shashank R. ; Hoyt, Kenneth ; Shaul, Philip W. ; Mineo, Chieko. / Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 1. pp. 309-322.
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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.",
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AU - Tanigaki, Keiji

AU - Sacharidou, Anastasia

AU - Peng, Jun

AU - Chambliss, Ken L.

AU - Yuhanna, Ivan S.

AU - Ghosh, Debabrata

AU - Ahmed, Mohamed

AU - Szalai, Alexander J.

AU - Vongpatanasin, Wanpen

AU - Mattrey, Robert F.

AU - Chen, Qiushi

AU - Azadi, Parastoo

AU - Lingvay, Ildiko

AU - Botto, Marina

AU - Holland, William L.

AU - Kohler, Jennifer J.

AU - Sirsi, Shashank R.

AU - Hoyt, Kenneth

AU - Shaul, Philip W.

AU - Mineo, Chieko

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N2 - 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.

AB - 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.

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