atherosclerosis

Leptinandatherosclerosis:acausallink?GUYONNETUlrichM2PHEDUEBIO531GCardiovascularandintegratedmetabolism1Context:atherosclerosisCardiovasculardiseases:17millionsdeathsComplicationsofatherosclerosis:mostcommoncausesofdeathinWesternsocieties2Context:atherosclerosisEndogenousfactorsExogenousfactorsHypertensionExerciseDiabetesLifestyleObesityNutritionInsulinoresistanceLDLVLDLHDLTable1:Riskfactorsofatherosclerosis3Context:adiposetissueBrownadiposetissue:abundantinnewbornsroleinthermogenesisWhiteadiposetissue:15-25%bodyweightstorage4Context:adiposetissueAdipocytesPreadipocytesEndothelialcellsCollagenfibrematrixMacrophagesLymphocytes5Context:adipocyteLipogenesisSettingasideoffattyacidsLipolysisMobilizationofreserveshormonalcontrolbypancreas6Shi,2004Context:adiposetissue7Mattu,2012Leptin:satietyhormone1stadipokinediscovered-16kDa-hormoneencodedbyobgenecirculatesasfreeandbound:1-4ng/ml6isoformsEncodedbydbgeneactionsmediatedby:•JAK/STAT•AMPK•PI3-Akt•MAPKpathways80.1nMLeptinglucoseproductionFAoxidationGlucoseutilizationinsulinsecretionlipogenesislipolysisfoodintake9Improveimmunity10PLASMAADIPOSETISSUELeptinlevelcorrelatesdirectlywiththemassofwhiteATLeptinactsto:reducefoodintakeincreaseenergyutilisationimproveimmunesystemANTI-OBESITYHORMONELönnqvist,199711PURPOSE?Determinethelinkbetweentheleptinhormoneandinductionofatherosclerosis12MCP-1=monocytechemoattractantprotein-1Yamagishi,2001BAECS[leptin]=10ng/mLLeptininducesupregulatevariousmediatorsofvascularinflammationandalsoTNFα,IL2-6…13LeptinpromotesaccumulationoflipoproteinsinsubendothelialspaceMaingrette,2008Humanmacrophagecellline[Leptin]=10nmol/l14Oda,2001LeptinstimulatesproliferationandmigrationofSMCOB-RisfoundinSMCLeptinSMCproliferationandmigrationSMCfromratthoracicaorta15LeptinincreasesplateletactivityandalsoPAI-1,vWF,tPA,plasmafibrinogen1:500ng/mLleptin2:2µMADP3:500ng/mLleptin+2µMADPElbatarny,200516FirstconclusionLeptininhighrateexertsmanypotentiallyatherogeniceffects:endothelialdysfunctionstimulationofinflammatoryreactionoxidativestressplateletaggregationandadhesionmigration,hypertrophyandproliferationofvascularsmoothmusclecells17Aim:Investigatetheassociationofleptinandsolubleleptinreceptorwithatherosclerosisinpatientswithdiabetetype2Methods:317type2diabeticsubjectsparticipatedinthisstudy.Theintima-mediathicknessoftheircommoncarotidarterywasmeasuredbyultrasound18Type2Diabete:non-insulindependentLossofsensitivityofcellstoinsulin(85%)INSULINRESISTANCEINSULINOPENIALeptin?19Subjectswasdividedin2groups20Leptinandleptin/sOb-RratioweresignificantcontributorstoIMTforInsulinuser21Leptin,sOb-Randleptin/sOb-RratiowereindependanttoIMTforInsulinnonuser22SecondconclusionCloseassociationofplasmaleptinandleptin/sOb-RwiththeIMTofthecarotidarteryintype2diabeticpatientstreatedwithinsulinHyperleptinemiaandexogenoustherapeuticinsulininteracttoaccelerateatheroscleroticprocessLimits:Japanesepatientsonlyvarioustreatments23Aim:InvestigatethephysiologicroleofleptininlipidmetabolismandatherosclerosisinT1DiabeteMethods:ThroughtIns2+/Akita:apoE-/-mousemodel24Type1Diabete:insulindependentInsulindeficiencybydestructionofpancreaticβcells(15%)setaside=weightlossPlasmaFFAandketonebodiesacidosishyperventilationGlucoseglucosuriaOsmolaritydehydrationpolyuria,thirst,weightloss25Ins2+/Akita:apoE-/-mousemodelType1DiabeteHypercholesterolemiaatherosclerosisSegar,201126Ins2+/Akita:apoE-/-mousemodelIns2+/Akita:apoE-/-27Leptintherapydecreasesatherosclerosislesion28Leptintherapyattenuatedhypercholesterolemia29ThirdconclusionLeptindeficiencyplaysaroleatherogenesisinType1diabeteTherapywithlowdoseleptinwouldlimittheprogressionofatheroscleroticplaquebydecreasingLDLcholesterol30ThebigconclusionHyperleptinemiacontributestotheformationofanatheroscleroticplaquebyactingonseveralcelltypesIntype2Diabete,hyperleptinemiaassociateswithinsulintreatmentfacilitateatherosclerosisIntype1Diabete,hypoleptinemiaalsocontributestoatherogenesisbutlowdoseletpintreatmentcanslowdownthisprocess31Context:obesityAnabnormalaccumulationorexcessivebodyfatthatmayimpairhealth32SynthesizedintheliverandtransportedalongwithHDLintheplasma.Itfunctionsasanantioxidant;itpreventstheoxidationofLDL.Itsserumconcentrationisinfluencedbyinflammatorychangesandthelevelsofserumoxidised-LDL.leptindecreasesparaoxonaseactivity33