Hyposialylated IgG Activates Endothelial IgG Receptor FcγRIIB to Promote Obesity-Induced Insulin Resistance

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dc.contributor.authorTanigaki, K.en_US
dc.contributor.authorSacharidou, A.en_US
dc.contributor.authorPeng, J.en_US
dc.contributor.authorChambliss, K. L.en_US
dc.contributor.authorYuhanna, I. S.en_US
dc.contributor.authorGhosh, Debabrataen_US
dc.contributor.authorAhmed, M.en_US
dc.contributor.authorSzalai, A. J.en_US
dc.contributor.authorVongpatanasin, W.en_US
dc.contributor.authorMattrey, R. F.en_US
dc.contributor.authorChen, Q.en_US
dc.contributor.authorAzadi, P.en_US
dc.contributor.authorLingvay, I.en_US
dc.contributor.authorBotto, M.en_US
dc.contributor.authorHolland, W. L.en_US
dc.contributor.authorKohler, J. J.en_US
dc.contributor.authorSirsi, Shashank R.en_US
dc.contributor.authorHoyt, Kennethen_US
dc.contributor.authorShaul, P. W.en_US
dc.contributor.authorMineo, C.en_US
dc.contributor.utdAuthorGhosh, Debabrataen_US
dc.contributor.utdAuthorSirsi, Shashank R.en_US
dc.contributor.utdAuthorHoyt, Kennethen_US
dc.date.accessioned2018-11-05T21:14:22Z
dc.date.available2018-11-05T21:14:22Z
dc.date.created2017-11-27en_US
dc.date.issued2018-11-05
dc.description.abstractType 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_US
dc.description.departmentErik Jonsson School of Engineering and Computer Scienceen_US
dc.description.sponsorshipAmerican Diabetes Association grant 1-10-BS-124; American Heart Association grant 13GRNT16080003; Cancer Prevention Research Institute of Texas (CPRIT) (RR150010); and NIH grants R01DK110127, R01HL115122, T32 HL098040, R01DK099092, K23 RR024470, 1S10 OD018530, P41GM10349010, R01DK108833, R01GM090271, K25EB017222 and R21CA212851.en_US
dc.identifier.bibliographicCitationTanigaki, 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/JCI89333en_US
dc.identifier.issn0021-9738en_US
dc.identifier.issue1en_US
dc.identifier.urihttp://hdl.handle.net/10735.1/6294
dc.identifier.volume128en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.urihttp://dx.doi.org/10.1172/JCI89333en_US
dc.rights©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.”en_US
dc.rights.urihttps://www.jci.org/kiosks/termsen_US
dc.source.journalJournal of Clinical Investigationen_US
dc.subjectPolysaccharidesen_US
dc.subjectImmunoglobulin Gen_US
dc.subjectInsulinen_US
dc.subjectSialoglycoproteinsen_US
dc.subjectEndotheliumen_US
dc.subjectInsulin Resistanceen_US
dc.subjectDiabetes Mellitus, Type 2en_US
dc.subjectObesityen_US
dc.subjectPathogenesisen_US
dc.subjectTranscytosisen_US
dc.subjectReceptors, IgGen_US
dc.titleHyposialylated IgG Activates Endothelial IgG Receptor FcγRIIB to Promote Obesity-Induced Insulin Resistanceen_US
dc.type.genrearticleen_US

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