Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance | Nature Metabolism

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Abstract

Metabolisminmammalsisregulatedbycomplexinterplayamongdifferentorgans.Fattyacidsynthesisisincreasedinwhiteadiposetissue(WAT)whenitisinhibitedintheliver.Hereweidentifyglycoproteinnon-metastaticmelanomaproteinB(Gpnmb)asoneliver鈥揥ATcross-talkfactorinvolvedinlipogenesis.Inhibitionofthehepaticsterolregulatoryelement-bindingproteinpathwayleadstoincreasedtranscriptionofGpnmbandpromotesprocessingofthemembraneproteintoasecretedform.GpnmbstimulateslipogenesisinWATandexacerbatesdiet-inducedobesityandinsulinresistance.Inhumans,Gpnmbistightlyassociatedwithbodymassindexandisastrongriskfactorforobesity.Gpnmbinhibitionbyaneutralizingantibodyorliver-specificknockdownimprovesmetabolicparameters,includingweightgainreductionandincreasedinsulinsensitivity,probablybypromotingthebeigingofWAT.TheseresultssuggestthatGpnmbisaliver-secretedfactorregulatinglipogenesisinWAT,andthatGpnmbinhibitionmayprovideatherapeuticstrategyinobesityanddiabetes.

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Fig.1:CompensatoryelevationoflipogenicgenesinWATfromL-Scap鈭?鈭?/i>orL-gp78鈭?鈭?/i>mice.

Fig.2:Gpnmbisproteolyticallycleavedandsecretedfromtheliver,andadenovirus-mediatedexpressionofGpnmbdrivesfatty-acid-synthesisgeneexpressioninWAT.

Fig.3:Gpnmb-ECDstimulatestheAKTsignallingpathwayviaCD44inadipocytes.

Fig.4:GpnmbincreaseslipogenesisinWAT.

Fig.5:Gpnmbpromotesdiet-inducedobesityandinsulinresistance.

Fig.6:EffectsofGpnmbneutralizationonDIOmice.

ThemicroarraydatasetdescribedinthepaperhasbeendepositedintheGeneExpressionOmnibusdatabasewithaccessionnumberGSE129283.Thedatathatsupportthefindingsofthisstudyareavailablefromthecorrespondingauthoruponreasonablerequest.

References1.

Finucane,M.M.etal.National,regional,andglobaltrendsinbody-massindexsince1980:systematicanalysisofhealthexaminationsurveysandepidemiologicalstudieswith960country-yearsand9.1millionparticipants.Lancet377,557鈥?67(2011).

ArticleGoogleScholar2.

Brown,M.S.Goldstein,J.L.Lipoproteinreceptorsintheliver.Controlsignalsforplasmacholesteroltraffic.J.Clin.Invest.72,743鈥?47(1983).

CASArticleGoogleScholar3.

Kuriyama,H.etal.CompensatoryincreaseinfattyacidsynthesisinadiposetissueofmicewithconditionaldeficiencyofSCAPinliver.CellMetab.1,41鈥?1(2005).

CASArticleGoogleScholar4.

Stefan,N.Haring,H.U.Theroleofhepatokinesinmetabolism.Nat.Rev.Endocrinol.9,144鈥?52(2013).

CASArticleGoogleScholar5.

Meex,R.C.etal.FetuinBisasecretedhepatocytefactorlinkingsteatosistoimpairedglucosemetabolism.CellMetab.22,1078鈥?089(2015).

CASArticleGoogleScholar6.

Gong,Y.etal.Sterol-regulatedubiquitinationanddegradationofInsig-1createsaconvergentmechanismforfeedbackcontrolofcholesterolsynthesisanduptake.CellMetab.3,15鈥?4(2006).

CASArticleGoogleScholar7.

Brown,M.S.Goldstein,J.L.Cholesterolfeedback:fromSchoenheimer鈥檚bottletoScap鈥檚MELADL.J.LipidRes.50,S15鈥揝27(2009).

ArticleGoogleScholar8.

Sun,L.P.,Seemann,J.,Goldstein,J.L.Brown,M.S.Sterol-regulatedtransportofSREBPsfromendoplasmicreticulumtoGolgi:InsigrenderssortingsignalinScapinaccessibletoCOPIIproteins.Proc.NatlAcad.Sci.USA104,6519鈥?526(2007).

CASArticleGoogleScholar9.

Horton,J.D.Sterolregulatoryelement-bindingproteins:transcriptionalactivatorsoflipidsynthesis.Biochem.Soc.Trans.30,1091鈥?095(2002).

CASArticleGoogleScholar10.

Hua,X.etal.SREBP-2,asecondbasic-helix-loop-helix-leucinezipperproteinthatstimulatestranscriptionbybindingtoasterolregulatoryelement.Proc.NatlAcad.Sci.USA90,11603鈥?1607(1993).

CASArticleGoogleScholar11.

Miserez,A.R.,Cao,G.,Probst,L.C.Hobbs,H.H.Structureofthehumangeneencodingsterolregulatoryelementbindingprotein2(SREBF2).Genomics40,31鈥?0(1997).

CASArticleGoogleScholar12.

Liu,T.F.etal.Ablationofgp78inliverimproveshyperlipidemiaandinsulinresistancebyinhibitingSREBPtodecreaselipidbiosynthesis.CellMetab.16,213鈥?25(2012).

CASArticleGoogleScholar13.

Lee,J.N.,Song,B.,DeBose-Boyd,R.A.Ye,J.Sterol-regulateddegradationofInsig-1mediatedbythemembrane-boundubiquitinligasegp78.J.Biol.Chem.281,39308鈥?9315(2006).

CASArticleGoogleScholar14.

Song,B.L.,Sever,N.DeBose-Boyd,R.A.Gp78,amembrane-anchoredubiquitinligase,associateswithInsig-1andcouplessterol-regulatedubiquitinationtodegradationofHMGCoAreductase.Mol.Cell19,829鈥?40(2005).

CASArticleGoogleScholar15.

Meex,R.C.R.Watt,M.J.Hepatokines:linkingnonalcoholicfattyliverdiseaseandinsulinresistance.Nat.Rev.Endocrinol.13,509鈥?20(2017).

CASArticleGoogleScholar16.

Azimifar,S.B.,Nagaraj,N.,Cox,J.Mann,M.Cell-type-resolvedquantitativeproteomicsofmurineliver.CellMetab.20,1076鈥?087(2014).

CASArticleGoogleScholar17.

Rose,A.A.etal.ADAM10releasesasolubleformoftheGPNMB/Osteoactivinextracellulardomainwithangiogenicproperties.PLoSONE5,e12093(2010).

ArticleGoogleScholar18.

Yu,B.,Sondag,G.R.,Malcuit,C.,Kim,M.H.Safadi,F.F.Macrophage-associatedosteoactivin/GPNMBmediatesmesenchymalstemcellsurvival,proliferation,andmigrationviaaCD44-dependentmechanism.J.CellBiochem.117,1511鈥?521(2016).

CASArticleGoogleScholar19.

Takashima,M.,Ogawa,W.,Emi,A.Kasuga,M.RegulationofSREBP1cexpressionbymTORsignalinginhepatocytes.KobeJ.Med.Sci.55,E45鈥揈52(2009).

CASPubMedGoogleScholar20.

Yecies,J.L.etal.AktstimulateshepaticSREBP1candlipogenesisthroughparallelmTORC1-dependentandindependentpathways.CellMetab.14,21鈥?2(2011).

CASArticleGoogleScholar21.

Duncan,R.E.,Ahmadian,M.,Jaworski,K.,Sarkadi-Nagy,E.Sul,H.S.Regulationoflipolysisinadipocytes.Annu.Rev.Nutr.27,79鈥?01(2007).

CASArticleGoogleScholar22.

Feng,B.etal.Clodronateliposomesimprovemetabolicprofileandreducevisceraladiposemacrophagecontentindiet-inducedobesemice.PLoSONE6,e24358(2011).

CASArticleGoogleScholar23.

Gao,G.P.etal.Noveladeno-associatedvirusesfromrhesusmonkeysasvectorsforhumangenetherapy.Proc.NatlAcad.Sci.USA99,11854鈥?1859(2002).

CASArticleGoogleScholar24.

Hong,J.etal.Geneticsusceptibility,birthweightandobesityriskinyoungChinese.Int.J.Obes.37,673鈥?77(2013).

CASArticleGoogleScholar25.

Rao,R.R.etal.Meteorin-likeisahormonethatregulatesimmune-adiposeinteractionstoincreasebeigefatthermogenesis.Cell157,1279鈥?291(2014).

CASArticleGoogleScholar26.

Kodama,K.etal.Expression-basedgenome-wideassociationstudylinksthereceptorCD44inadiposetissuewithtype2diabetes.Proc.NatlAcad.Sci.USA109,7049鈥?054(2012).

CASArticleGoogleScholar27.

Weiss,L.etal.Inductionofresistancetodiabetesinnon-obesediabeticmicebytargetingCD44withaspecificmonoclonalantibody.Proc.NatlAcad.Sci.USA97,285鈥?90(2000).

CASArticleGoogleScholar28.

Kodama,K.,Toda,K.,Morinaga,S.,Yamada,S.Butte,A.J.Anti-CD44antibodytreatmentlowershyperglycemiaandimprovesinsulinresistance,adiposeinflammation,andhepaticsteatosisindiet-inducedobesemice.Diabetes64,867鈥?75(2015).

CASArticleGoogleScholar29.

Dodd,G.T.etal.LeptinandinsulinactonPOMCneuronstopromotethebrowningofwhitefat.Cell160,88鈥?04(2015).

CASArticleGoogleScholar30.

Ruan,H.B.etal.O-GlcNActransferaseenablesAgRPneuronstosuppressbrowningofwhitefat.Cell159,306鈥?17(2014).

CASArticleGoogleScholar31.

Zhu,Y.etal.Connexin43mediateswhiteadiposetissuebeigingbyfacilitatingthepropagationofsympatheticneuronalsignals.CellMetab.24,420鈥?33(2016).

CASArticleGoogleScholar32.

Zhou,Q.L.etal.MembraneTraffickingProteinCDP138RegulatesFatBrowningandInsulinSensitivitythroughControllingCatecholamineRelease.Mol.Cell.Biol.38,e00153-17(2018).

ArticleGoogleScholar33.

Kitamura,T.etal.Insulin-inducedphosphorylationandactivationofcyclicnucleotidephosphodiesterase3Bbytheserine-threoninekinaseAkt.Mol.Cell.Biol.19,6286鈥?296(1999).

CASArticleGoogleScholar34.

Dickson,L.M.,Gandhi,S.,Layden,B.T.,Cohen,R.N.Wicksteed,B.ProteinkinaseAinducesUCP1expressioninspecificadiposedepotstoincreaseenergyexpenditureandimprovemetabolichealth.Am.JPhysiol.Regul.Integr.Comp.Physiol.311,R79鈥揜88(2016).

ArticleGoogleScholar35.

Fredriksson,J.M.etal.AnalysisofinhibitionbyH89ofUCP1geneexpressionandthermogenesisindicatesproteinkinaseAmediationofbeta(3)-adrenergicsignallingratherthanbeta(3)-adrenoceptorantagonismbyH89.Biochim.Biophys.Acta1538,206鈥?17(2001).

CASArticleGoogleScholar36.

Anderson,M.G.etal.MutationsingenesencodingmelanosomalproteinscausepigmentaryglaucomainDBA/2Jmice.Nat.Genet.30,81鈥?5(2002).

CASArticleGoogleScholar37.

Ripoll,V.M.etal.MicrophthalmiatranscriptionfactorregulatestheexpressionofthenovelosteoclastfactorGPNMB.Gene413,32鈥?1(2008).

CASArticleGoogleScholar38.

Abdelmagid,S.M.etal.OsteoactivinactsasdownstreammediatorofBMP-2effectsonosteoblastfunction.J.Cell.Physiol.210,26鈥?7(2007).

CASArticleGoogleScholar39.

Schwarzbich,M.A.etal.Theimmuneinhibitoryreceptorosteoactivinisupregulatedinmonocyte-deriveddendriticcellsbyBCR-ABLtyrosinekinaseinhibitors.CancerImmunol.Immunother.61,193鈥?02(2012).

CASArticleGoogleScholar40.

Choi,M.S.etal.High-fatdietdecreasesenergyexpenditureandexpressionofgenescontrollinglipidmetabolism,mitochondrialfunctionandskeletalsystemdevelopmentintheadiposetissue,alongwithincreasedexpressionofextracellularmatrixremodelling-andinflammation-relatedgenes.Br.J.Nutr.113,867鈥?77(2015).

CASArticleGoogleScholar41.

Kuan,C.T.etal.GlycoproteinnonmetastaticmelanomaproteinB,apotentialmoleculartherapeutictargetinpatientswithglioblastomamultiforme.Clin.CancerRes.12,1970鈥?982(2006).

CASArticleGoogleScholar42.

Okamoto,I.etal.Sevennovelandstabletranslocationsassociatedwithoncogenicgeneexpressioninmalignantmelanoma.Neoplasia7,303鈥?11(2005).

CASArticleGoogleScholar43.

Rose,A.A.etal.Osteoactivinpromotesbreastcancermetastasistobone.Mol.CancerRes.5,1001鈥?014(2007).

CASArticleGoogleScholar44.

Zhou,L.T.etal.Gpnmb/osteoactivin,anattractivetargetincancerimmunotherapy.Neoplasma59,1鈥?(2012).

CASArticleGoogleScholar45.

Choi,C.H.J.Cohen,P.Adiposecrosstalkwithothercelltypesinhealthanddisease.Exp.CellRes.360,6鈥?1(2017).

CASArticleGoogleScholar46.

Zhang,Y.etal.Positionalcloningofthemouseobesegeneanditshumanhomologue.Nature372,425鈥?32(1994).

CASArticleGoogleScholar47.

Maeda,K.etal.cDNAcloningandexpressionofanoveladiposespecificcollagen-likefactor,apM1(AdiPosemostabundantGenetranscript1).Biochem.Biophys.Res.Commun.221,286鈥?89(1996).

CASArticleGoogleScholar48.

Long,J.Z.etal.ThesecretedenzymePM20D1regulateslipidatedaminoaciduncouplersofmitochondria.Cell166,424鈥?35(2016).

CASArticleGoogleScholar49.

Feve,B.,Bastard,C.,Fellahi,S.,Bastard,J.P.Capeau,J.Newadipokines.Ann.Endocrinol.(Paris)77,49鈥?6(2016).

ArticleGoogleScholar50.

Bostrom,P.etal.APGC1-alpha-dependentmyokinethatdrivesbrown-fat-likedevelopmentofwhitefatandthermogenesis.Nature481,463鈥?68(2012).

ArticleGoogleScholar51.

Hondares,E.etal.HepaticFGF21expressionisinducedatbirthviaPPARalphainresponsetomilkintakeandcontributestothermogenicactivationofneonatalbrownfat.CellMetab.11,206鈥?12(2010).

CASArticleGoogleScholar52.

Fisher,F.M.etal.FGF21regulatesPGC-1alphaandbrowningofwhiteadiposetissuesinadaptivethermogenesis.GenesDev.26,271鈥?81(2012).

CASArticleGoogleScholar53.

Xie,T.Leung,P.S.Fibroblastgrowthfactor21:aregulatorofmetabolicdiseaseandhealthspan.Am.J.Physiol.Endocrinol.Metab.313,E292鈥揈302(2017).

ArticleGoogleScholar54.

Seale,P.etal.Prdm16determinesthethermogenicprogramofsubcutaneouswhiteadiposetissueinmice.J.Clin.Invest.121,96鈥?05(2011).

CASArticleGoogleScholar55.

Liao,Y.C.etal.Thenon-canonicalNF-kappaBpathwaypromotesNPC2expressionandregulatesintracellularcholesteroltrafficking.Sci.ChinaLifeSci.61,1222鈥?232(2018).

CASArticleGoogleScholar56.

Ferre,P.,Leturque,A.,Burnol,A.F.,Penicaud,L.Girard,J.Amethodtoquantifyglucoseutilizationinvivoinskeletalmuscleandwhiteadiposetissueoftheanaesthetizedrat.Biochem.J.228,103鈥?10(1985).

CASArticleGoogleScholar57.

Liu,R.etal.Rareloss-of-functionvariantsinNPC1predisposetohumanobesity.Diabetes66,935鈥?47(2017).

CASArticleGoogleScholar58.

Wang,J.etal.AblationofLGR4promotesenergyexpenditurebydrivingwhite-to-brownfatswitch.Nat.CellBiol.15,1455鈥?463(2013).

CASArticleGoogleScholar

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Acknowledgements

WethankH.-H.Miao,Y.-X.Qu,J.Xu,D.Liang,B.-Y.XiangandY.Y.Liufortechnicalassistance,Y.-K.SunforhumansamplecollectionandY.Heforstatisticalanalysis.ThisworkwassupportedbygrantsfromtheNationalNaturalScienceFoundation(China;Nos.31430044,31690102,91857000and81522011),MinistryofScienceandTechnology(China;No.2016YFA0500100),theScienceandTechnologyDepartmentofHubeiProvince(No.2016CFA012)andthe111ProjectoftheMinistryofEducationofChina(No.B16036).

AuthorinformationAuthornotes

Theseauthorscontributedequally:Xue-MinGong,Yun-FengLi,JieLuo,Ji-QiuWang,JianWei.

AffiliationsHubeiKeyLaboratoryofCellHomeostasis,CollegeofLifeSciences,InstituteforAdvancedStudies,WuhanUniversity,Wuhan,ChinaXue-MinGong,聽Yun-FengLi,聽JieLuo,聽JianWei,聽Ju-QiongWang,聽TingXiao,聽Xiong-JieShi聽聽Bao-LiangSongTheStateKeyLaboratoryofMolecularBiology,InstituteofBiochemistryandCellBiology,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,Shanghai,ChinaXue-MinGong,聽ChangXie聽聽Bo-LiangLiSchoolofLifeScienceandTechnology,ShanghaiTechUniversity,Shanghai,ChinaXue-MinGong聽聽WeiQiShanghaiClinicalCenterforEndocrineandMetabolicDiseases,DepartmentofEndocrinologyandMetabolism,StateKeyLaboratoryofMedicalGenomes,RuijinHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,ChinaJi-QiuWang,聽JieHong聽聽GuangNingAuthorsXue-MinGongViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarYun-FengLiViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJieLuoViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJi-QiuWangViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJianWeiViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJu-QiongWangViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarTingXiaoViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarChangXieViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJieHongViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarGuangNingViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarXiong-JieShiViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarBo-LiangLiViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarWeiQiViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarBao-LiangSongViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarContributions

B.-L.S.conceivedtheproject.X.-M.G.,Y.-F.L.,G.N.,J.-Q.W.,J.W.,B.-L.L.,W.Q.andB.-L.S.designedtheexperiments.X.-M.G.,Y.-F.L.,J.-Q.W.,T.X.,J.W.,C.X.andJ.H.performedtheexperiments.X.-M.G.,Y.-F.L.,J.L.andB.-L.S.analyzedthedata.J.-Q.W.providedandanalyzedthehumanserumsamples.X.-M.G.,Y.-F.L.,J.L.,W.Q.andB.-L.S.wrotethepaper,withinputfromothers.

Correspondingauthors

CorrespondencetoWeiQiorBao-LiangSong.

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