心肌素相關轉(zhuǎn)錄因子調(diào)控米色脂肪細胞的產(chǎn)生_第1頁
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心肌素相關轉(zhuǎn)錄因子調(diào)控米色脂肪細胞的產(chǎn)生第1頁，課件共34頁，創(chuàng)作于2023年2月Whiteadiposetissue

storesexcessenergyintheformoftriglycerides.BrownadiposetissuedissipatesenergyasheatviatheuniqueexpressionofthemitochondrialuncouplingproteinUCP1.Thedevelopmentaloriginofbeigeadipocytesisunclear.TheydefinatedaBMP7-ROCKsignalingaxisregulatingbeigeadipocyteformationviacontroloftheG-actin-regulatedtranscriptionalcoactivatormyocardin-relatedtranscriptionfactorA,MRTFA.Summary第2頁，課件共34頁，創(chuàng)作于2023年2月WhiteadiposetissuefromMRTFA–/–micecontainsmoremultilocularadipocytesandexpressesenhancedlevelsofbrown-selectiveproteins,includingUCP1.MRTFA–/–micealsoshowimprovedmetabolicprofilesandprotectionfromdiet-inducedobesityandinsulinresistance.Thestudyhenceunravelsacentralpathwaydrivingthedevelopmentofphysiologicallyfunctionalbeigeadipocytes.Summary第3頁，課件共34頁，創(chuàng)作于2023年2月1Introduction2Result3DiscussionCONTENTS第4頁，課件共34頁，創(chuàng)作于2023年2月IntroductionWhite&BrownadipocyteWhiteadipocytesstoreslipidsinuniloculardroplets,incomparison,brownadipocytescontainmultilocularlipiddropletsandnumerousmitochondria.Whiteadipocytesstoreexcessenergyintheformoftriglycerides,brownadipocytesarethermogeniccellsthat,whenactivatedbyappropriatestimuli,dissipateenergyasheat.UCP1UCP1isabrownadiposetissue(BAT)-specificmitochondrialuncouplingprotein,andtheactivityofitrelatedtoenergyrelease.第5頁，課件共34頁，創(chuàng)作于2023年2月IntroductionBeigeadipocyteUCP1+adipocytesdesignatedasbeigeadipocyte.Currenthypothesesproposethattheyarisefromthe

conversionofexistingwhiteadipocytesand/orthedifferentiationofWATresidentprogenitorcells.Brownandbeigeadipocytesinvitropossessadistinctgeneexpressionsignature.

theoriginsofprogenitorsPPARglineagetracingstudiesindicatedthatWATprogenitorsresideinthemuralcellcompartmentofadiposevasculatureandatleastapopulationofbeigecellshaveasmoothmuscle-likeorigin.Theseobservationssuggestthatwhiteandbeigeadipocytesarisefromprogenitorscloselyassociatedwiththevasculature.第6頁，課件共34頁，創(chuàng)作于2023年2月IntroductionTGFbTGF??superfamilyintimatelyregulatesthedevelopmentandmaintenanceofthevasculatureviapromotingsmoothmuscledifferentiationandcoordinatingtheexpressionofSMCgenes.Italsoinhibitsadipocytedifferentiationviaitscoeffector,Smad3,whichcomplexeswithC/EBP??andrepressesactivationofadipogenictargetgenes.Smad3knockout(KO)micedevelopbrown-likeadipocytesinWATdepotsandareprotectedfromobesity.BMP7Bonemorphogeneticproteins(BMPs),promoteadipocyteformation.BMP7initiatesthecommitmentofMSCstothebrownadipocytelineagebypromotingtheexpressionofthebrownadipocytefactorsPRDM16,PGC-1aandUCP1,andmitochondrialbiogenesis.Importantly,BMP7-/-miceattenuatestheformationofBAT;BMP7isalsoabletoinducetheconversionofprogenitorsisolatedfromWAT,BAT,andmuscletobrown-likeadipocyte.第7頁，課件共34頁，創(chuàng)作于2023年2月SRF/MRTFspathwayTheRho-GTPasefamilymediatesthedynamiccontrolofmonomericandfilamentousactin.MonomericG-actincanregulatethenucleus-cytoplasmshuttlingofserumresponsefactor(SRF)coregulators,myocardin-relatedtranscriptionfactors(MRTFs)and,thereby,influencetheexpressionofSRFtargetgenesincludingsmoothmuscleactin(SMA).Introduction第8頁，課件共34頁，創(chuàng)作于2023年2月1Introduction2Result3DiscussionCONTENTS第9頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第10頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第11頁，課件共34頁，創(chuàng)作于2023年2月ResultBMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

C3h/10T1/2MSCsdifferentiation.?BMP7?MSCs?adipocytes?TGF???MSCs?muscle-likecells第12頁，課件共34頁，創(chuàng)作于2023年2月ResultBMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

Bonemarrow-derivedMSCs.TGFb1alsoactivatedSMADs1/5/8indicatingthatBMP7-inducedcommitmentisnotmediatedexclusivelybyactivationoftheSMADs,butbyadditionaldownstreameffectorsoftheBMPreceptor.第13頁，課件共34頁，創(chuàng)作于2023年2月ResultBMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

DMH1:inhibitorofBMPreceptorsGremlin1:inhibitorofBMP7SMAD1/5/8↓p38MAPK↓BMP7&receptoractivatedpathwaytogether.第14頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第15頁，課件共34頁，創(chuàng)作于2023年2月ResultBMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.BMP7-treatedcells:abroadenedshapeandalessprominentactinnetwork;TGFb1-treatedcells:anelongatedmorphologyandformationofactinmicrofilaments.?BMP7?MSCs?ROCKactivity↓(pMYPT1↓,ROCK'starget)?TGF???MSCs?ROCKactivity↑(pMYPT1↑)?

Thechangeofactindynamics?ROCK第16頁，課件共34頁，創(chuàng)作于2023年2月ResultBMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.ROCKactivitydeclinedrapidlyduringBMP7-inducedbrownadipogenesisreachingundetectablelevelsinmatureadipocytes.ConsistentwithitsinhibitionofROCK,biochemicalandcellstainingassaysrevealedthatBMP7increasedtheG/F-actinratio.TheROCKinhibitorY27632similarlyenhancedG-actinlevelsrelativetoF-actin.第17頁，課件共34頁，創(chuàng)作于2023年2月ResultInhibitionoftheROCK/SRFPathwayEnhancesBrownAdipogenesisinMSCs.?Y27632couldmimictheeffectsofBMP71)Y27632aloneonlyhasamodesteffectonadipocytegeneexpressionandonnumberofcellsconvertingtoadipocytesthatcouldbeNileRedstained.2)Y27632didpotentiatetheactionofBMP7.(PPAR??,FABP4↑)ROCKinhibitionpartiallyovercametheinhibitoryeffectofGremlinonadipocytegeneanddifferentiationwhilehavinglimitedeffectsonUCP1expression.?Y27632couldnotexactly

mimicBMP7.★第18頁，課件共34頁，創(chuàng)作于2023年2月ResultInhibitionoftheROCK/SRFPathwayEnhancesBrownAdipogenesisinMSCs.?CCG1423?MSCs?enhanceconversiontoadipocytes,andinduceexpressionofbrownadipocytesgenes.?

TheproadipogenicactivityofBMP7involvessuppressionofMRTF/SRFactivity★CCG1423didnotaltertheactincytoskeleton.?CCG1423blocksSRFdownstreamofF-actinpolymerization.?CCG1423couldmimicBMP7.★第19頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第20頁，課件共34頁，創(chuàng)作于2023年2月ResultMRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.?C3H/10T1/2MSCsdifferentiatetoadipocytes:TheexpressionofMRTFA,MRTFB,SRF,andSMA,collagen1a1,collagen3a1(SRFtargetgenes)↓TheexpressionofFABP4,UCP-1↑第21頁，課件共34頁，創(chuàng)作于2023年2月ResultMRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.?EctopicallyexpressSRForMRTFA:ThedifferentiationofMSCstoadipocytes↓Theexpressionofselectwhiteandbrownadipogenicgenes↓?theROCK-SRFpathwayisanimportantBMP7target

?ROCK-SRF↓

?adipogenesis↑?CCG1423couldpartiallyrescuedtheinhibitoryeffectofMRTFAorSRFonadipocyteformation.第22頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第23頁，課件共34頁，創(chuàng)作于2023年2月Result?KOmouse●iWAT:moremultilocularadipocytes●eWAT:fewmultilocularadipocytes,smalleradipocytes.●BAT:nomorphologicalorUCP1expressionchanges.?WTmouse●iWAT:hypertrophy.Biggerindividualunilocularadipocytes.?Bodyweightdepotmorphology?KOmouse●Lessweight&lessoverallfatmassrelativetoleanmass(6weeksoflowfatdiet).●Lowerfastinglevelsofglucose,butnodifferencesinglucose(aGTT).●Lowercirculatinglevelsofleptin&higherlevelsofadiponectinandinsulin.IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.第24頁，課件共34頁，創(chuàng)作于2023年2月ResultIncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.?RNAanalysis?iWATofKOmouse?moreexpressionofUCP1mRNA?moreexpressionofotherbrownadipocytemRNAs?BATofKOmouse?n.s.withWTmouseinUCP1mRNA,buthigherthaniWAT.

?WATgenes?AgtLowerlevelsofexpressioninKOmouseiWAT&higherdevelopmentofbrown-likeadipocytesinKOmouseiWAT?SMALowerlevelsofexpressioninKOmouseiWAT?Tbx1(amarkerofbeigeadipocyte)HigherlevelsofexpressioninKOmouseiWAT?theappearanceofUCP1positive,multilocularadipocytesinKOmiceislikelyduetorecruitmentofbeigeprogenitors.第25頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第26頁，課件共34頁，創(chuàng)作于2023年2月ResultStromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFCells.

?

MRTFArepressesbeigeadipocyteformationdirectly?SVFsofWTandKOiWAT?adipocytes(invitro)

?comparableexpressionofadiponectin,adipsin,FABP4.?approximatelythesameextent.

?KOSVFs:selectBATproteins(UCP1,Chchd10/NDG2)↑

?FSK?adipocytes?expressionofUCP1mRNA(WT&KO)

?UCP1,Fabp3,Cidea,Cox7a1,andElovl3?(KO)?somebeigeadipocyteshaveasmoothmuscle-likeorigin.第27頁，課件共34頁，創(chuàng)作于2023年2月ResultStromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFCells.

?BMP7?SVFs?MRTFA,CRP2,SMA,andcalponin↓★theKOSVFcells:loweramountofSMproteins

?TGF??

?SVFs?SMprotein↑?BMP7directsSVFprogenitorstoabeigeadipocytelineageratherthanaSMlineage.第28頁，課件共34頁，創(chuàng)作于2023年2月1BMP7andTGFbmediatedistincteffectsonlineagecommitmentofMSCsthroughalterationofROCKactivity.

。2BMP7RepressesROCKActivityandAltersActinDynamicsinMSCs.3MRTFAandSRFOverexpressionPreventDifferentiationofMSCstoAdipocytes.Results4IncreasedProductionofBeigeAdipocytesinWATofMRTFA-DeficientMice.5StromalVascularCellsfromMRTFA–/–iWATUndergoBeigeAdipogenesisMoreExtensivelyThanWTSVFs.

6MRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.

。7MRTFARegulatesWhole-BodyEnergyExpenditure.第29頁，課件共34頁，創(chuàng)作于2023年2月ResultMRTFA-DeficientMiceAreProtectedfromDiet-InducedObesityandInsulinResistance.?HFD:high-fatdietStartat6weeksagefor6weeks.?KO???lessweight?lessfatmass?lessiWAT&eWATweight,nosignificantchangeinBAT?lessliverweight?mayduetotheextensiveaccumulationofhepaticlipidinWTmice.?lowerlevelsoffastingglucose?enhancedglucosetolerance?lowercirculatinglevelsofleptin?lessfat&highercirculatinglevelsofadiponectin?nosignofexcesslipiddepositionintheindividualadipocytesofiWATandeWAT?iWATproducedabundantamountsofUCP1&otherbrowngenes?areductionincrown-likestructuresintheeWAT?KOmicewereprotectedfromdiet-inducedinflammation

?MRTFAdeficiencyreducesHFD-inducedobesity,insulinresistance,eWATinfl

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