exosomal and insulin sensitivityp外泌体与胰岛素敏感性

AdiposeTissueMacrophage-DerivedExosomalmiRNAsCanModulateInVivoandInVitroInsulinsensitivityGuang-yaZhangNov.18th,2017Howtoreadapaper?title/abstractauthorCurrentresearchprogress(introduction/scientificproblems)Researchproject(results)ConclusionanddiscussionJerroldOlefskyTitle ProfessorSchool UniversityofCalifornia,SanDiegoDepartmentMedicineSaltielAR,OlefskyJ.Inflammatorymechanismslinkingobesityandmetabolicdisease.JClinInvest.2017Jan03;127(1):1-4.McNelisJC,OlefskyJ.Macrophages,immunity,andmetabolicdisease.Immunity.2014Jul17;41(1):36-48.PMID:25035952LeeYS,KimJW,OsborneO,OhDY,SasikR,SchenkS,ChenA,ChungH,MurphyA,WatkinsSM,QuehenbergerO,JohnsonRS,OlefskyJ.IncreasedadipocyteO2consumptiontriggersHIF-1a,causinginflammationandinsulinresistanceinobesity.Cell.2014Jun05;157(6):1339-52.LeeB,QiaoL,LuM,YooHS,CheungW,MakR,SchaackJ,FengGS,ChiNW,OlefskyJ,ShaoJ.C/EBParegulatesmacrophageactivationandsystemicmetabolism.AmJPhysiolEndocrinolMetab.2014May15;306(10):E1144-54.LiP,SpannNJ,KaikkonenMU,LuM,OhDY,FoxJN,BandyopadhyayG,TalukdarS,XuJ,LagakosWS,PatsourisD,ArmandoA,QuehenbergerO,DennisEA,WatkinsSM,AuwerxJ,GlassCK,OlefskyJ.NCoRrepressionofLXRsrestrictsmacrophagebiosynthesisofinsulin-sensitizingomega3fattyacids.Cell.2013Sep26;155(1):200-214.PMID:24074869;PMCID:PMC4131699.FangS,SuhJM,ReillySM,YuE,OsbornO,LackeyD,YoshiharaE,PerinoA,JacintoS,LukashevaY,AtkinsAR,KhvatA,SchnablB,YuRT,BrennerDA,CoulterS,LiddleC,SchoonjansK,OlefskyJ,SaltielAR,DownesM,EvansRM.IntestinalFXRagonismpromotesadiposetissuebrowningandreducesobesityandinsulinresistance.NatMed.2015Feb;21(2):159-65.Inokuchi-ShimizuS,ParkEJ,RohYS,YangL,ZhangB,SongJ,LiangS,PimientaM,TaniguchiK,WuX,AsahinaK,LagakosW,MackeyMR,AkiraS,EllismanMH,SearsDD,OlefskyJ,KarinM,BrennerDA,SekiE.TAK1-mediatedautophagyandfattyacidoxidationpreventhepatosteatosisandtumorigenesis.JClinInvest.2014Aug;124(8):3566-78.RavnskjaerK,HoganMF,LackeyD,ToraL,DentSY,OlefskyJ,MontminyM.GlucagonregulatesgluconeogenesisthroughKAT2B-andWDR5-mediatedepigeneticeffects.JClinInvest.2013Oct;123(10):4318-28.ReillySM,ChiangSH,DeckerSJ,ChangL,UhmM,LarsenMJ,RubinJR,MowersJ,WhiteNM,HochbergI,DownesM,YuRT,LiddleC,EvansRM,OhD,LiP,OlefskyJ,SaltielAR.AninhibitoroftheproteinkinasesTBK1andIKK-bimprovesobesity-relatedmetabolicdysfunctionsinmice.NatMed.2013Mar;19(3):313-21.McNelisJC,LeeYS,MayoralR,vanderKantR,JohnsonAM,WollamJ,OlefskyJ.GPR43Potentiatesß-CellFunctioninObesity.Diabetes.2015Sep;64(9):3203-17.OhDY,WalentaE,AkiyamaTE,LagakosWS,LackeyD,PessentheinerAR,SasikR,HahN,ChiTJ,CoxJM,PowelsMA,DiSalvoJ,SinzC,WatkinsSM,ArmandoAM,ChungH,EvansRM,QuehenbergerO,McNelisJ,Bogner-StraussJG,OlefskyJ.AGpr120-selectiveagonistimprovesinsulinresistanceandchronicinflammationinobesemice.NatMed.2014Aug;20(8):942-7.XuJ,MorinagaH,OhD,LiP,ChenA,TalukdarS,MamaneY,ManciniJA,NawrockiAR,LazarowskiE,OlefskyJ,KimJJ.GPR105ablationpreventsinflammationandimprovesinsulinsensitivityinmicewithdiet-inducedobesity.JImmunol.2012Aug15;189(4):1992-9.LiP,LiuS,LuM,BandyopadhyayG,OhD,ImamuraT,JohnsonAM,SearsD,ShenZ,CuiB,KongL,HouS,LiangX,IovinoS,WatkinsSM,YingW,OsbornO,WollamJ,BrennerM,OlefskyJ.Hematopoietic-DerivedGalectin-3CausesCellularandSystemicInsulinResistance.Cell.20161103;167(4):973-984.e12.LiP,OhDY,BandyopadhyayG,LagakosWS,TalukdarS,OsbornO,JohnsonA,ChungH,MarisM,OfrecioJM,TaguchiS,LuM,OlefskyJM.LTB4promotesinsulinresistanceinobesemicebyactingonmacrophages,hepatocytesandmyocytes.NatMed.2015Mar;21(3):239-247.SuhJM,JonkerJW,AhmadianM,GoetzR,LackeyD,OsbornO,HuangZ,LiuW,YoshiharaE,vanDijkTH,HavingaR,FanW,YinYQ,YuRT,LiddleC,AtkinsAR,OlefskyJ,MohammadiM,DownesM,EvansRM.EndocrinizationofFGF1producesaneomorphicandpotentinsulinsensitizer.Nature.2014Sep18;513(7518):436-9LeeYS,MorinagaH,KimJJ,LagakosW,TaylorS,KeshwaniM,PerkinsG,DongH,KayaliAG,SweetIR,OlefskyJ.Thefractalkine/CX3CR1systemregulatesßcellfunctionandinsulinsecretion.Cell.2013Apr11;153(2):413-25.StellaKourembanas.Annu.Rev.Physiol.2015.77:7.1–7.15

Exosomeshaveadiameterof30–100nm,adensityof1.13–1.19g/mLandatypicalcup-shapedappearance.Background

Typicalstructureandcontentofexosomes.Exosomesaresurroundedbyaphospholipidbilayerandcontainproteins,suchasannexins,thatareimportantfortransport;tetraspaninsforcelltargeting;andotherproteins,suchasAlixandTSG101,thatareinvolvedinexosomalbiogenesisfromendosomes.StellaKourembanas.Annu.Rev.Physiol.2015.77:7.1–7.15

Exosomesaresecretedthroughfusionofmultivesicularbodieswiththeplasmamembraneandcarryacargothatincludesproteins,DNA,andRNA.Intracellularuptakeofexosomesoccursviaendocytosis,membranefusion,orreceptor-mediatedinternalization.StellaKourembanas.Annu.Rev.Physiol.2015.77:7.1–7.15

ExosomesderivedfrompancreaticcancercellsinduceinsulinresistanceinC2C12myotubecellsthroughthePI3K/Akt/FoxO1pathway.WangL,ZhangB,ZhengW,KangM,ChenQ,QinW,LiC,ZhangY,ShaoY,WuY.SciRep.2017Jul14;7(1):5384.DengZB,PoliakovA,HardyRW,etal.Adiposetissueexosome-likevesiclesmediateactivationofmacrophage-inducedinsulinresistance.Diabetes.2009;58:2498–2505.Thomou,T.,Mori,M.A.,Dreyfuss,J.M.,Konishi,M.,Sakaguchi,M.,Wolfrum,C.,Rao,T.N.,Winnay,J.N.,Garcia-Martin,R.,Grinspoon,S.K.,etal.(2017).Adipose-derivedcirculatingmiRNAsregulategeneexpressioninothertissues.Nature542,450–455.AtheroprotectivecommunicationbetweenendothelialcellsandsmoothmusclecellsthroughmiRNAs.HergenreiderE,HeydtS,TréguerK,BoettgerT,HorrevoetsAJ,ZeiherAM,SchefferMP,FrangakisAS,YinX,MayrM,BraunT,UrbichC,BoonRA,DimmelerS.NatCellBiol.2012Feb12;14(3):249-56.KapustinAN,ChatrouML,DrozdovI,etal.Vascularsmoothmusclecellcalcifcationismediatedbyregulatedexosomesecretion.CircRes.2015;116:1312–1323.NiuC,WangX,ZhaoM,CaiT,LiuP,LiJ,WillardB,ZuL,ZhouE,LiY,PanB,YangF,ZhengL.Macrophagefoamcell-derivedextracellularvesiclespromotevascularsmoothmusclecellmigrationandadhesion.JAmHeartAssoc.2016;5(10):pii:e004099.1.DoesATMsSecreteExosomalmiRNAs?2.WhatistheroleofATM-DerivedmiRNA-ContainingExosininsulinresistance?ATM-DerivedExosfromObeseMiceATM-DerivedExosfromLeanMiceinvivoandinvitrosystemicglucosehomeostasisinsulinsignalpathwayadiposeandmuscleglucoseuptakeliverglycogensis3.WhichcomponentofATM-DerivedExosplaysamajorroleinObesityinducedInsulinResistanceExosmiRNAseqMiR-155(targetPPARγ-GLUT4)invitroandinvivo(chimericmice)ATMsSecreteExosomalmiRNAs

ResultsNanosightanalysis技术利用光散射和布朗运动的特性获得液体悬浮液中的样本粒度分布。DEVsecretioninhibitorGW4869ThePKH26FluorescentCellLinkerKitsuseproprietarymembranelabelingtechnologytostablyincorporateayellow-orangefluorescentdyewithlongaliphatictails(PKH26)intolipidregionsofthecellmembrane.ATM-DerivedmiRNA-ContainingExosfromObeseMicePromoteInsulinResistancesensitivenormalchowdiet(NCD)-fedWTleanmicewereusedasrecipientsandwereintravenouslyinjectedwithPKH26-labeledATM-Exos(30mgevery7days)derivedfromobeseanimals(obeseATM-Exos)ObeseATM-ExosomalmiRNAsImpairCellularInsulinSensitivityDrosha(anessentialpoly