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首页 脂肪起源

脂肪起源

脂肪起源

soso_snow
2013-12-11 0人阅读 举报 0 0 暂无简介

简介:本文档为《脂肪起源pdf》,可适用于自然科学领域

inAAdipocyteprogenitorprecursorLipodystrophytennerAT)e)mestsndltpfromaprecursorsharedwithskeletalmusclethatexpressesMyfCre,whileallsesincloccurssetissulyvaributiondisorderscharacterizedbyregionallipoatrophywithotherdepotsWATdepotandthereforedepotnamesoftenvarybetweenstudiesBiochimicaetBiophysicaActaxxx()xxx–xxxBBADISNoofpages:C:,,,ContentslistsavailableatSciVerseScienceDirectBiochimicaetBielsbeingsparedorevenexpanding,Withaworldwideobesityepidemicwellunderway,thestudyofadiposetissuegrowth,distribution,andregulationisamajorresearchfocusYetthedevelopmentaloriginsoffat,thedeterminantsofbodyfatdistribution,andthesignalingmechanismsthatcontrolfatgrowthremainpoorlydefinedAdiposetissueiscomplexandheterogeneousAccordingto,WATdepotsinrodentsincludetheanteriorsubcutaneousWATs(asWATs)includinginterscapularandaxillaryWAT(locatedinthescapularregion),inguinalWAT(ingWATattacheddorsallyalongthepelvistothethighofthehindlimb),perigonadalWAT(pgWATsurroundingtheuterusandovariesinfemalesandtheepididymisandtestesinmales),retroperitonealWAT(rWATlocatedwithintheabdominalcavityalongthedorsalwalloftheabdomenbehindthekidneybutnotattachedtothekidneyormixedwithperirenalbrownfat),Inmammals,fatistypicallyclassifiedbyanceasbeingeitherwhiteadiposetissue(W☆ThisarticleispartofaSpecialIssueentitled:ModulatandDisease⁎CorrespondingauthorTel:Emailaddress:davidguertinumassmededu(DA$–seefrontmatter©ElsevierBVAllhttp:dxdoiorgjbbadisPleasecitethisarticleas:JSanchezGurmachttp:dxdoiorgjbbadismorefavorablemetabolicsalsopresentasfatdistritrunkcavity)orsubcutaneous(belowtheskin)ThereisnotauniformlyappliedsystemfordescribingtheanatomicallocationofeachandnotallfatisequalwithsomedepotshavingpropertiesthanothersSomelipodystrophieIntroduction:Obesityisariskfactorformanydiseadiovasculardisease,andcancerObesityceedsenergyexpenditurecausingadipobodyfatdistributionpatternsarehighwhyBATismoremetabolicallyfavorablethanWAT,recentworkindicatesthesituationismorecomplexbecausesubsetsofwhiteadipocytesalsoarisefromMyfCreexpressingprecursorsLineagetracingstudiesfurthersuggestthatthevasculaturemayprovideanichesupportingbothbrownandwhiteadipocyteprogenitorshowever,theidentityoftheadipocyteprogenitorcellisunderdebateDifferencesinoriginbetweenadipocytescouldexplainmetabolicheterogeneitybetweendepotsandorinfluencebodyfatpatterningparticularlyinlipodystrophydisordersHere,wediscussrecentinsightsintoadiposetissueoriginshighlightinglineagetracingstudiesinmice,howvariationsinmetabolismorsignalingbetweenlineagescouldaffectbodyfatdistribution,andthequestionsthatremainunresolvedThisarticleispartofaSpecialIssueentitled:ModulationofAdiposeTissueinHealthandDisease©ElsevierBVAllrightsreservedudingtypediabetes,carwhenenergyintakeexetoovergrowHowever,ablebetweenindividualstissue(BAT)WAT(theprimarysiteofenergystorage)ismostlycomposedofadipocytescontainingalargeunilocularlipiddropletWATsarefoundthroughoutthebodyhowever,thedistributionofmassbetweeneachdepotvariesinthepopulationasafunctionofgenetics,age,andforsomedepots,sensitivitytohormonesandglucocorticoidsWATlocationisoftenclassifiedasbeingvisceral(intheBriteorbeigeadipocyteMyfwhiteadipocytesoriginatefromaMyfnegativeprecursorsWhilethisprovidedarationalexplanationtoWhiteadiposetissue(WAT)Brownadiposetissue(BAT)brownadipocytesoriginateAdipocytelineages:TracingbacktheorigJoanSanchezGurmaches,DavidAGuertin⁎PrograminMolecularMedicine,UniversityofMassachusettsMedicalSchool,Worcester,MabstractarticleinfoArticlehistory:ReceivedFebruaryReceivedinrevisedformMayAcceptedMayAvailableonlinexxxxKeywords:TheobesityepidemichasinopmentAdiposetissueisgeorbrownadiposetissue(Badipocytes(browninwhitexistinadulthumanssuggcombatobesityTounderstaadipocytesbacktotheiraduReviewjournalhomepage:wwwmorphologicalappearAT)orbrownadiposeionofAdiposeTissueinHealthGuertin)rightsreservedhes,DAGuertin,Adipocytelisoffat☆,USAsifiedeffortstounderstandthemechanismscontrollingadiposetissuedevelallyclassifiedaswhiteadiposetissue(WAT),themajorenergystoringtissue,,whichmediatesnonshiveringthermogenesisItishypothesizedthatbriteayrepresentathirdadipocyteclassTherecentrealizationthatbrownfatincreasingbrownfatenergyexpenditurecouldbeatherapeuticstrategytoadiposetissuedevelopment,severalgroupsaretracingtheoriginsofmaturerecursorandembryonicancestorsFromthesestudiesemergedamodelthatophysicaActaeviercomlocatebbadisandmesentericWAT(mWATliningthesurfaceoftheintestines)(Fig)AlthoughtheprimaryfunctionofWATisenergystorage,italsofunctionsasanendocrineorgansecretinghormonesandcytokinessuchasleptinandadiponectinthatregulatefeedingandmetabolismEpidemiologicalstudieshavefoundthattheaccumulationofvisceralfat(determinedbyhighwaisttohipratio)associateswithmetabolicdisease(ieinsulinresistance,typediabetes,dyslipidemia,neages:Tracingbacktheoriginsoffat,BiochimBiophysActa(),JSanchezGurmaches,DAGuertinBiochimicaetBiophysicaActaxxx()xxx–xxxhypertension,atherosclerosis,hepaticsteatosis,andcancer)whiletheaccumulationofsubcutaneousWATassociateswithimprovedinsulinsensitivityandlowriskfordevelopingtypediabetes–Brownadipocytescontainmultiplesmaller(multilocular)lipiddroplets,arerichinmitochondria,andresideindepotsthatarehighlyinnervatedandvascularizedInrodents,BATislocatedindiscretedepotsininterscapular(iBAT),subscapular(sBAT),andcervical(cBAT)FigTheMyflineagecontributiontotheprecursorpoolineachfatdepotvarieswithitsanatomicallocationThecontributionoftheMyflineagetotheadipocyteprecursorcellcompartment(definedasCD−CD−Terr−CDCDScacells)wasrecentlydeterminedbylineagetracingwithMyfCreRRYFPmiceMorethanoftheprecursorsinbrownfatarelabeledwithMyfCreIntheanteriorsubcutaneousWATs(includinginterscapularandaxialWATs)nearlyoftheprecursorstracetoMyfprecursors,andintherWAT(avisceralWAT),theMyfprecursorsgiverisetoapproximatelyoftheadipocyteprecursorcellpoolIncontrast,theMyflineagecontributesverylittletotheadipocyteprecursorpooliningWATandpgWAT,whichare–MyfnegThecontributionoftheMyflineagetotheintramuscularadipogenicprecursorpool(definedwithslightlydifferentcellsurfacemarkers)isverylowDottedlineindicatestheabdominalcavityReferencesprovidedinthetextregionsoftheupperanteriorsideofthetrunkandneck(Fig)BATalsogrowsaroundpartsoftheaortaandkidneysThesedepotsareoftencalled“classical”BATtodistinguishthemfrombrownadipocytelikecells,calledbriteadipocytes,whichresidewithinsomeWATs(discussedbelow)Incontrasttoenergystoringwhiteadipocytes,brownadipocytesarespecializedtoexpendenergytogenerateheatinaprocesscalledadaptivethermogenesisBATisstimulatedbythesympatheticnervoussystemfollowingexposuretocoldtemperatureandregulatestheacutenonshiveringthermogenesisresponseaswellastheadaptivecoldacclimatizationresponsefollowingchroniccoldexposureThermogenesisismeditatedbyuncouplingprotein(UCP),whichembedsintheinnermitochondrialmembrane,andproducesheatbydissipatingtheprotonelectrochemicalgradientovertheintermitochondrialmembranespacewithoutgeneratingATPBATstoresenergyforthermogenesisasperilipincoatedlipiddropletsandglycogengranules,anduponstimulationrapidlyincreasesglucoseandFAuptaketoreplenishitssuppliesThehighglucoseuptakecapacityofBATmakesitreadilydetectablebyFfluorodeoxyglucosepositronemissiontomography(FDG–PET),,Whilelongthoughttobecriticalonlyinrodentsandnewbornhumans,therecentrealizationthatBATfunctionsinadulthumans(madepossiblebyitssensitivitytoFDG–PET)–raisesthepossibilitythattherapeuticallycontrollingBATgrowthandorenergyexpenditurecouldbeastrategytocombatobesity–Interestisalsogrowinginathirdpotentialclassofadipocytecalledabriteadipocyte(alsoknownasa“beige”,“induciblebrown”,or“recruitablebrown”adipocyte),,–ThismysterioustypeofadipocyteexistsamongclassicalwhiteadipocytesandismorphologicallyindistinguishablefromitsneighboringwhiteadipocytesinthebasalorunstimulatedstateHowever,uponstimulationbychroniccoldexposure(orothermechanismsthatmimicbetaadrenergicPleasecitethisarticleas:JSanchezGurmaches,DAGuertin,Adipocytelihttp:dxdoiorgjbbadisstimulation)theybecomemultilocularandbeginexpressingUCP,,,ThepresenceofbriteadipocytesintheWATofmiceisnothomogeneousForexample,manyadipocytesiningWATorrWATbecomemultilocularandinduceUCPfollowingstimulationhowever,onlyafewUCPbriteadipocytesariseinpgWATinthesamemice,Briteadipocytecontentvariesbetweenmousestrainsandcorrelateswithoverallstrainsensitivitytohighfatdiet–Whetherbriteadipocytesformbytransdifferentiationofexistingwhiteadipocytesorarisefromauniquepreadipocytelineageisunderdebate(discussedbelow),,,–PerhapsthebiggestunresolvedissuepertainingtobriteadipocytesiswhetherthesecellsactuallycontributesignificantlytothermogenesisForexample,whileUCPmRNAisinducedinbriteadipocytesseveralhundredfoldrelativetowhiteadipocytes(whichbarelyexpressesUCP),,,thetotalUCPexpressionisstillanorderofmagnitudelowerthanthatdetectedinbrownadiposetissueInfact,themaximumthermogeniccapacityofbritefathasbeenestimatedatonly~ofclassicalbrownfatinmiceAdebateisunderwayastowhetherhumanbrownfatismoresimilartobritefatortoclassicalbrownfatinmiceEarlyreportsarguethatwhatiscurrentlybeingcalledhumanbrownfatismoresimilartomurinebritefatthantoclassicalmurinebrownfat,However,recentstudiesthatmoreextensivelyprofiledifferentlayersofadiposetissueinnewbornsandadultsrevealsthathumanshavebrownfatdepositsparticularlyintheneckthathaveaclassicbrownfatsignature,Interestingly,thereappearstobeagradientoffatcelltypesintheneck,withdeepneckfatbeingclassicalBAT,intermediatecellspossiblybeingmorebritelike,andthemostperipheraladipocytesbeingclassicalwhiteadipocytesThesefindingsareimportantconsideringthegrowingemphasisondevelopingtherapeuticstrategiestoinducethe“browning”ofWATinhumans,–becausetheysuggestthatthestudiesofclassicalbrownfatinmicecouldalsohaveimportanttherapeuticimplicationsinhumansThephysiologicalsignificanceandregulatorymechanismsofbrownversusbritefatinhumansclearlyneedtobedeterminedEachindividualfatdepotiscomplex,composednotonlyofmatureadipocytesbutalsoofadipocyteprecursorcells,fibroblasts,nerves,vascularcells,macrophages,andothercelltypes(collectivelycalledthestromalvascularfractionorSVF)AddingtotheircomplexityisthefactthatadiposetissuesarefunctionallyheterogeneousAlthoughthesharpestfunctionaldivergenceisclearlybetweenenergystoringWATandenergyexpendingBAT,functionaldivergenceisalsoevidentbetweenWATsbestexemplifiedbytheriskassociatedwithexcessvisceralfatversussubcutaneousfatHowever,suchsimpledistinctionsareoversimplificationsbecausedifferencesinlipogenicactivity,celldynamics,proliferativeanddifferentiationcapacity,andgeneexpressionevenbetweencategoricallysimilarWATdepotshavebeenreported–HeterogeneitylikelyexistsevenwithinasingleWATassuggestedbystudiesshowingthatneighboringadipocytescanresponddifferentlytogeneticperturbationsordrugs–Theexistenceofsuchheterogeneitywithinandbetweenfattissuessuggestsbroadconclusionsshouldnotbebasedonalimitedsurveyofselectfatdepots,andthateachdepotshouldbeconsideredseparatelyDoesadipocytetissueheterogeneityreflectdifferentdevelopmentaloriginsofadipocytes,variancesinthedevelopmentalcuesaparticularadipocytemayexperienceduringdifferentiation,orextracellularinfluencesonthematureadipocytesuniquetothelocalcellortissueenvironmentAnsweringthesequestionscouldleadtonewantiobesitytherapies,improvetheunderstandingoflipodystrophies,andincreasetheprospectofusingadipocyteprogenitorcellsforcellbasedtherapeutics,,TheoriginofadipocytesCentraltounderstandingthecomplexitiesandheterogeneityofadiposetissueistounderstandwherethepathtobecominganneages:Tracingbacktheoriginsoffat,BiochimBiophysActa(),TableSummaryofrecentlineagetracingstudiesofpreandmatureadipocytesGeneticapproachPromoterlocationRationaleReportedresultReferencesWhiteadipocytessoxCreRReYFPTransgeneSoxexpressesinpreandmigratoryneuralcrestcellsatallrostrocaudallevelsMatureadipocytesinthesalivaryglandlabeledpositivepgWATandingWATlabelednegative,PPARγtTATRECreRRLacZKnockinPPARγisanuclearreceptorexpressedinalltissuesandiscriticalforadipogenesisingWATandrWATpositivesomepositiveSVFcellsaPGFPTransgeneaP(FABP)expressesinmatureadipocytesandisatargetofPPARγingWATpositiveaPCreRRLacZTransgeneDescribedaboveingWATandpgWATpositivePDGFRβCreRRLacZTransgenePDFGRβisexpressedinvascularmuralcellsingWATandrWATpositive,myfCreRReYFPKnockinMyfisamuscledifferentiationtranscriptionfactorthatisfirstexpressedinthedermomyotomeatEandexpressesinadultsatellitecellsingWATandpgWATnegative,wntCreRReYFPTransgeneRestrictivemarkerofmigratingneuralcrestcellsCephalicWATpositivepgWATandingWATnegativeofadipocyteprecursorsincephalicWATpositiveallingWATadipocyteprecursorsnegative,LysMCreRRLacZKnockinThelysozymeMisexclusivelyexpressedinmacrophagesandgranulocytes–ofpgWATadipocytespositive,VEcadherinCreRRLacZKnockinVEcadherinisexpressedinendothelialcells,isinvolvedincelladhesion,andisessentialforvascularsystemdevelopmentingWATandpgWATpositive,VEcadherinCreRReGFPKnockinDescribedaboveSubsetofmatureadipocytesinthepgWATpositive,VEcadherinCreERTRRLacZKnockinVEcadherinCreERTisatamoxifeninducibleversionoftheVEcadherinCreNumerousadipocytesintheingWAT,pgWATandBATpositive,ZFPGFPKnockinZfpisatranscriptionalregulatorbroadlyexpressedbutessentialforpreadipocytecommitmentingWATpositivepaxCreRRmTmGKnockinPaxisamuscledifferentiationtranscriptionfactorfirstexpressedindorsalneuralcrestandsomitesitcooperateswithMyftodrivemuscledevelopmentoftheadipogenicSVFcellsfromasWATpositive,myfCreRRLacZKnockinDescribedaboveMatureadipocytesfromasWATandrWATpositivefewmatureadipocytesfromingWATandpgWATpositive–ofadipogenicSVFcellsfromasWATandrWATpositivebfromtheingWATandpgWATpositive,myfCreRReYFPKnockinDescribedabove–oftheadipocyteprecursorsfromasWATandrWATpositiveboftheadipocyteprecursorsfrompgWATandingWATpositive,vavCreRRmTmGKnockinVavisaprotooncogenethatexpressesinthehematopoieticandlymphoidsystemsAlladipocyteprecursorsandmatureadipocytesfromingWAT,pgWAT,rWATandmWATnegative,tieCreRRmTmGTransgeneTieisanangiopoietinreceptorspecifictoendothelialcellsandsomehematopoieticcellsAlladipocyteprecursorsandmatureadipocytesfromingWAT,pgWAT,rWATandmWATnegative,VEcadherinCreRRmTmGKnockinDescribedaboveAlladipocyteprecursorsandmatureadipocytesfromingWAT,pgWAT,rWATandmWATnegative,PDFGRαCreRRmTmGTransgenePDGFRαisexpressedinmostmesenchymalcellscanactivatetheMAPK,PIKandPLCγsignalingpathwaysAlladipocyteprecursorsandmatureadipocytesfromingWAT,pgWAT,rWATandmWATpositive,BrownadipocytesEnCreRRLacZKnockinEngrailedisahomeoboxtranscriptionfactorthatexpressesincellsofthecentraldermomyotomeBATpositive,myfCreRReYFPKnockinDescribedaboveBATpositive,paxCreERTRRLacZKnockinPaxisexpressedinmedialandcentralcellsofthedermomyotomeandinadultsatellitecellsBATpositive,myfCreRRLacZKnockinDescribedaboveBATpositive>ofadipogenicBATSVFcellspositive,myfCreRReYFPKnockinDescribedabove>ofBATadipocyteprecursorspositive,VEcadherinCreRRLacZKnockinDescribedaboveBATpositive,VEcadherinCreERTRRLacZKnockinDescribedaboveManybrownadipocytespositive,BriteadipocytesmyfCreRReYFPKnockinDescribedaboveBriteadipocytesiningWATnegative,myfCreRRLacZKnockinDescribedaboveCL,inducedbriteadipocytesinasWATandrWATpositivebriteadipocytesinducediningWATnegative,VEcadherinCreERTRRLacZKnockinDescribedaboveRosiglitazoneinducedbrightadipocytesiningWATpositive,UCPCreERTRRtdRFPKnockinUCPisthemostacceptedfunctionalmarkerofbrownadipocytesBriteandwhiteadipocytesinterconvertiningWATdependingonthetemperature(continuedonnextpage)JSanchezGurmaches,DAGuertinBiochimicaetBiophysicaActaxxx()xxx–xxxPleasecitethisarticleas:JSanchezGurmaches,DAGuertin,Adipocytelineages:Tracingbacktheoriginsoffat,BiochimBiophysActa(),http:dxdoiorgjbbadisJSanchezGurmaches,DAGuertinBiochimicaetBiophysicaActaxxx()xxx–xxxadipocytebeginsMoreover,strategiestargetingnascentadipocytescouldbeusefulinfightingobesityhowevertheidentityoftheadipocyteprogenitorcellsisjustbeginningtobeunraveledAsobesityprogresses,adiposetissuesgrowbyhypertrophy(increasingthesizeoftheiradipocytes)andbyhyperplasia(increasingthenumberofadipocytes)–Ayearlyadipocyteturnoverrateforleanandobesehumansofhasbeenreported,butbecausematureadipocytesdonotdivide,aresidentadipocyteprecursorcellmustexistUndifferentiatedadipocyteprogenitorcellswerelongassumedto

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