Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity

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dc.contributor.authorShi, Haoen
dc.contributor.authorMunk, Alexanderen
dc.contributor.authorNielsen, Thomas S.en
dc.contributor.authorDaughtry, Morgan R.en
dc.contributor.authorLarsson, Louiseen
dc.contributor.authorLi, Shizeen
dc.contributor.authorHoyer, Kasper F.en
dc.contributor.authorGeisler, Hannah W.en
dc.contributor.authorSulek, Karolinaen
dc.contributor.authorKjobsted, Rasmusen
dc.contributor.authorFisher, Tayloren
dc.contributor.authorAndersen, Marianne M.en
dc.contributor.authorShen, Zhengxingen
dc.contributor.authorHansen, Ulrik K.en
dc.contributor.authorEngland, Eric M.en
dc.contributor.authorCheng, Zhiyongen
dc.contributor.authorHojlund, Kurten
dc.contributor.authorWojtaszewski, Jorgen FP P.en
dc.contributor.authorYang, Xiaoyongen
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorHelm, Richard F.en
dc.contributor.authorTreebak, Jonas T.en
dc.contributor.authorGerrard, David E.en
dc.date.accessioned2021-11-03T14:23:36Zen
dc.date.available2021-11-03T14:23:36Zen
dc.date.issued2018-05-01en
dc.date.updated2021-11-03T14:23:32Zen
dc.description.abstractObjective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders.en
dc.description.versionPublished versionen
dc.format.extentPages 160-177en
dc.format.extent18 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.molmet.2018.02.010en
dc.identifier.eissn2212-8778en
dc.identifier.issn2212-8778en
dc.identifier.orcidGerrard, David [0000-0002-3482-1400]en
dc.identifier.orcidHelm, Richard [0000-0001-5317-0925]en
dc.identifier.otherS2212-8778(17)31100-6 (PII)en
dc.identifier.pmid29525407en
dc.identifier.urihttp://hdl.handle.net/10919/106502en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000439548700014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectEndocrinology & Metabolismen
dc.subjectO-GlcNAc signalingen
dc.subjectType 2 diabetesen
dc.subjectN-acetyl-D-glucosamineen
dc.subjectTissue cross talken
dc.subjectEpigenetic regulation of Il15 transcriptionen
dc.subjectInsulin sensitivityen
dc.subjectADIPOSE-TISSUEen
dc.subjectGLUCOSE-UPTAKEen
dc.subjectINTERLEUKIN-15en
dc.subjectRESISTANCEen
dc.subjectOBESITYen
dc.subjectGLCNACYLATIONen
dc.subjectIL-15en
dc.subjectAMPKen
dc.subjectMETABOLISMen
dc.subjectMODULATIONen
dc.subject0601 Biochemistry and Cell Biologyen
dc.subject0606 Physiologyen
dc.subject.meshMuscle, Skeletalen
dc.subject.meshAdipose Tissueen
dc.subject.meshAnimalsen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshDiabetes Mellitus, Type 2en
dc.subject.meshInsulin Resistanceen
dc.subject.meshN-Acetylglucosaminyltransferasesen
dc.subject.meshInterleukin-15en
dc.subject.meshHomeostasisen
dc.subject.meshEnhancer of Zeste Homolog 2 Proteinen
dc.titleSkeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivityen
dc.title.serialMolecular Metabolismen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2018-02-19en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Animal and Poultry Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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