Rab4b Is a Small GTPase Involved in the Control of the Glucose Transporter GLUT4 Localization in Adipocyte 英文参考文献.docVIP

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Rab4b Is a Small GTPase Involved in the Control of the Glucose Transporter GLUT4 Localization in Adipocyte 英文参考文献.doc

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Rab4b Is a Small GTPase Involved in the Control of the Glucose Transporter GLUT4 Localization in Adipocyte 英文参考文献

Rab4bIsaSmallGTPaseInvolvedintheControlofthe GlucoseTransporterGLUT4LocalizationinAdipocyte VincentKaddai1,2,TeresaGonzalez1,2,Fre′de′riqueKeslair1,2,ThierryGre′meaux1,2,Ste′phanie Bonnafous2,3,4,JeanGugenheim2,3,4,AlbertTran2,3,4,PhilippeGual2,3,4,YannickLeMarchand- Brustel1,2,3,4,MireilleCormont1,2 * 1INSERMU895,CentreMe′diterrane′endeMe′decineMole′culaire(C3M),Team7,CellularandMolecularPhysiopathologyofObesityandDiabetes,Nice,France,2Facultyof Medicine, University of Nice/Sophia-Antipolis, Nice, France, 3INSERM U895, Centre Me′diterrane′en de Me′decine Mole′culaire (C3M), Team 8, Hepatic Complications in Obesity,FacultyofMedicine,UniversityofNice/Sophia-Antipolis,Nice,France,4CHUofNice,Po?leDigestif,Ho?pitalArchet2,Nice,France Abstract Background:EndosomalsmallGTPasesoftheRabfamily,amongthemRab4a,playanessentialroleinthecontrolofthe glucosetransporterGLUT4trafficking,whichisessentialforinsulin-mediatedglucoseuptake.Wefoundthatadipocytesalso expressedRab4bandweobservedaconsistentdecreaseintheexpressionofRab4bmRNAinhumanandmiceadipose tissueinobesediabeticstates.TheseresultsledustostudythispoorlycharacterizedRabmemberanditspotentialrolein glucosetransport. Methodology/PrincipalFindings:Weused3T3-L1adipocytestostudybyimagingapproachesthelocalizationofRab4b andtodeterminetheconsequenceofitsdownregulationonglucoseuptakeandendogenousGLUT4location.Wefound thatRab4bwaslocalizedinendosomalstructuresinpreadipocyteswhereasinadipocytesitwaslocalizedinGLUT4andin VAMP2-positivecompartments,andalsoinendosomalcompartmentscontainingthetransferrinreceptor(TfR).WhenRab4b expressionwasdecreasedwithspecificsiRNAsbytwofold,anextentsimilartoitsdecreaseinobesediabeticsubjects,we observed a small increase (25%) in basal deoxyglucose uptake and a more sustained increase (40%) in presence of submaximal and maximal insulin concentrations. This increase occurred without any change in GLUT4 and GLUT1 expressionlevelsandintheinsulinsignalingpathways.Concomitantly,GLUT4butnotTfRamountswereinc