Tanigaki, K.Sacharidou, A.Peng, J.Chambliss, K. L.Yuhanna, I. S.Ghosh, DebabrataAhmed, M.Szalai, A. J.Vongpatanasin, W.Mattrey, R. F.Chen, Q.Azadi, P.Lingvay, I.Botto, M.Holland, W. L.Kohler, J. J.Sirsi, Shashank R.Hoyt, KennethShaul, P. W.Mineo, C.2018-11-052018-11-052017-11-272018-11-050021-9738http://hdl.handle.net/10735.1/6294Type 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.en©2017 American Society for Clinical Investigaiton. "The JCI is an open access journal. All research content is freely available immediately upon publication. Users are allowed to read, download, print, search, or link to the full texts of the articles under the "fair use" limitations of US copyright law.”https://www.jci.org/kiosks/termsPolysaccharidesImmunoglobulin GInsulinSialoglycoproteinsEndotheliumInsulin ResistanceDiabetes Mellitus, Type 2ObesityPathogenesisTranscytosisReceptors, IgGarticleTanigaki, K., A. Sacharidou, J. Peng, K. L. Chambliss, et al. 2018. "Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance." Journal of Clinical Investigation 128(1), 309-322, doi:10.1172/JCI893331281