147main14815120097271511426151page4531511 Incommemorationofthe75thanniversaryofEscolaPaulistadeMedicinaUniversidadeFederaldeS ID: 311126
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AnaisdaAcademiaBrasileiradeCiências(2009)81(3):453-466(AnnalsoftheBrazilianAcademyofSciences)ISSN0001-3765www.scielo.br/aabcMetabolismandsecretoryfunctionofwhiteadiposetissue:effectofdietaryfatCLÁUDIAM.OLLERDONASCIMENTO1,ELIANEB.RIBEIRO1andLILAM.OYAMA21DepartamentodeFisiologia,UniversidadeFederaldeSãoPaulo,CampusSãoPauloRuaBotucatu,862,2andar,04023-060SãoPaulo,SP,Brasil2DepartamentodeBiociências,UniversidadeFederaldeSãoPaulo,CampusBaixadaSantistaAv.AnaCosta,95,11060-001Santos,SP,BrasilManuscriptreceivedonAugust21,2008;acceptedforpublicationonFebruary2,2009;presentedbyLUIZR.TRAVASSOSABSTRACTApproximately40%ofthetotalenergyconsumedbywesternpopulationsisrepresentedbylipids,mostofthembeingingestedastriacylglycerolsandphospholipids.Thefocusofthisreviewistoanalyzetheeffectofthetypeofdietaryfatonwhiteadiposetissuemetabolismandsecretoryfunction,particularlyonhaptoglobin,TNF-,plasminogenactivatorinhibitor-1andadiponectinsecretion.Previousstudieshavedemonstratedthatthedurationoftheexposuretothehigh-fatfeeding,amountoffattyacidpresentinthedietandthetypeoffattyacidmayormaynothaveasignicanteffectonadiposetissuemetabolism.However,thelong-termorshort-termhighfatdiets,especiallyrichinsaturatedfattyacids,probablybyactivationoftoll-likereceptors,stimulatedtheexpressionofproinammatoryadipokinesandinhibitedadiponectinexpression.Furtherstudiesareneededtoinvestigatethecellularmechanismsbywhichdietaryfattyacidsaffectwhiteadiposetissuemetabolismandsecretoryfunctions.Keywords:adipokines,highfatdiets,metabolism,whiteadiposetissue.INTRODUCTIONWhiteadiposetissue(WAT)playsaroleinenergystor-ageandinsulationfromenvironmentaltemperatureandtrauma.Paleontologicalevidenceindicatesthattherapidbrainevolution,observedwiththeemergenceofHomoerectusatapproximately1.61.8millionyearsago,waslikelyassociatedwithincreasedbodyfatnessaswellasdietquality(Leonardetal.2003).Inthelongrun,whitefatmassreectsthenetbalancebetweenenergyexpen-ditureandenergyintake.Fatstorageoccursbothbythedirectuptakeofcirculatinglipoproteintriacylglyc-erols,whicharehydrolyzedbylipoproteinlipasetonon-esteriedfreefattyacids,andalsobylocallipogenicpathways,i.e.thedenovosynthesisfromglucoseand Incommemorationofthe75thanniversaryofEscolaPaulistadeMedicina/UniversidadeFederaldeSãoPaulo.Correspondenceto:Dr.CláudiaM.OllerdoNascimentoE-mail:claudia.oller@unifesp.brotherprecursors(Pénicaudetal.2000).Ontheotherhand,thistissuecanreleasebothfreefattyacidsandglycerol,providingcirculatingsubstratesforothertis-sues,accordingtotheirenergyneeds.Currently,ithasbeenrecognizedthatwhiteadiposetissueactsalsoasanendocrineorgan.Thistissuese-cretesproandanti-inammatoryproteinfactors,knownasadipokines.Theseadipokinesincludehormonesim-plicatedinenergybalance(e.g.,leptin,adiponectin),glu-cosetoleranceandinsulinsensitivity(adiponectin,re-sistin),classicalcytokines(e.g.,TNF-,interleukin-6),andproteinsinvolvedinlipidmetabolism(e.g.,lipopro-teinlipase,retinolbindingprotein),vascularhaemosta-sis(e.g.,plasminogenactivatorinhibitor-1andangio-tensinogen)andininammationandstressresponses(suchashaptoglobinandmetallothionein)(TrayhurnandBeattie2001,Mohamed-Alietal.1998,Frühbecketal.2001).AnAcadBrasCienc(2009)81(3) main2009/7/2714:26page454#2 454CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAThisreviewanalysestheimpactofdietaryfattyacidcompositiononadiposemetabolismandsecretoryfunction.METABOLISMOFWHITEADIPOSETISSUELIPOPROTEINLIPASEANDTRIACYLGLYCEROLMETABOLISMLipoproteinlipase(LPL)hasitsphysiologicalsiteofac-tionattheluminalsurfaceofcapillaryendothelialcells,wheretheenzymehydrolysesthetriacylglycerol(TAG)componentofcirculatinglipoproteinparticles,chylomi-cronsandverylowdensitylipoproteinstoprovidefreefattyacidsand2-monoacylglycerolfortissueutilization.LPLisdistributedinwiderangeoftissues(Cryer1981).Mostoftheplasmatriacylglycerolsareprovidedbydietarylipids,secretedfromtheintestineintheformofchylomicronorfromtheliverintheformofVLDL.Releasedintocirculationasnon-esteriedfattyacidsbylipoproteinlipase,thosearetakenupbyWATviaspecicplasmafattyacidtransporters(CD36,FATP,FABPpm)andusedfortriacylglycerolsynthesis(Largeetal.2004).LPLactivitycanbealteredinatissue-specicman-ner,whichisphysiologicallyimportantbecauseitdi-rectsfattyacidutilization,accordingtothemetabolicdemands,ofindividualtissues,sothatthedegradationoftriacylglycerol-richlipoproteinscanbetargetedtospe-cicsites.Forexample,weobservedadramaticincreaseinmammaryglandLPLactivitywithacorrespondingdecreaseinWATLPLactivityduringlactationtopro-videlipidformilksynthesis(OllerdoNascimentoandWilliamson1986).Ontheotherhand,aftertheremovalofthepups,theactivityofLPLinWATisincreasedconsiderablycomparedwithlactatingmammarygland,whichplayaroleinthereplenishmentofadiposetissuestores.StarvationandmalnutritiondecreasedLPLactivityinmammaryglandandWATandincreaseditinmuscle(OllerdoNascimentoandWilliamson1988,doCarmoetal.1996,Doolittleetal.1990,BraunandSever-son1992).Ontheotherhand,inthefedstate,theLPLactivityisincreasedinWATanddecreasedinmuscle.Thephysiologicalresultsareapreferentialdepositionoflipidintheadiposetissueafterameal,andsupplyenergytoskeletalmuscleduringfooddeprivation.TheplasmainsulinconcentrationseemstobemoreimportantthanprolactinincontrollingLPLactivityandlipiddepositioninWATduringlactationandafterwean-ing(OllerdoNascimentoetal.1989).InsulinincreasesLPLgeneexpressionandactivityinWATviaactivationofphosphatidylinositol3-kinase(PI3K)pathway(Kraemeretal.1998).GlucocorticoidsalsoincreasedLPLmRNAandLPLactivity.Takingto-gether,thesehormoneshaveasynergisticeffectatthelevelofLPLgeneexpression,aswellasposttranslation-ally(Friedetal.1993).Inthemonosodiumglutamatemodelofobesity(MSG-obese),ithasbeendemonstratedhyperinsuli-nemia(Sartinetal.1985)andhypercorticosteronemia(Ribeiroetal.1997,Dolnikoffetal.1988)accompa-niedbyanincreaseinWATLPLactivity(NascimentoCurietal.1991).LIPOGENESISdenovoThelipogenesisdenovoisanimportantpathwaytoconverttheexcessofcarbohydrateingestedtotriacyl-glyceroltobestoredintotheWAT.Physiologicalfac-torssuchasdieting/fastingregulatethismetabolicpath-way,whichisalsomodiedinpathologicalconditionse.g.obesity.Severaltissues(e.g.whiteandbrownadi-posetissue,liver,mammarygland)possessthecomple-mentofenzymesnecessaryfortheactivesynthesisoftriacylglycerol.Inhumans,theliverisresponsiblefortheconver-sionofexcessdietarycarbohydratesintofattyacids,throughlipogenesisdenovo(Denechaudetal.2008a).Asmallpartoftriacylglycerolsissynthesizedintoadi-pocytesfromcarbohydrates,butitsregulationisstilldebatedinhumans.Ontheotherhand,inrodents,theWATlipogenesisdenovoishigherthaninhumansandalsocouldberegulatedbynutritionalandhormonalconditions.Iritanietal.(1996)demonstratedthatthemRNAconcentrationsofacetyl-CoAcarboxylase,fattyacidsynthase(FAS)andATPcitrate-lyaseincreasedaftertherefeedinginWATandliverinrats.MSG-obeseratshaveahighWATandliverlipoge-nesisdenovorateascomparedtoleanones(NascimentoCurietal.1991).Inthisobesemodel,partialremovalofretroperitonealandepididymalWATcausedanincreaseinthelipogenesisdenovointhecarcass,epididymalandretroperitonealWAT,whichcouldhavecontributedAnAcadBrasCienc(2009)81(3) main2009/7/2714:26page455#3 DIETARYFATANDWHITEADIPOSETISSUE455forobservedfatmassreplenishmentandnewadipocytesdifferentiation(Buenoetal.2005).Theeffectofglucocorticoidonthelipogenesisdenovoiscontroversial.Apreviousstudyshowedthat,invivo,thishormonecausesadecreaseinlipogenicen-zymesactivityinwhiteadiposetissue(VolpeandMarasa1975);conversely,dexamethasoneincreasedtheactionofinsulinonacetil-CoAcarboxilasegeneexpressioninadipocytes(TraversandBarber1999).Itiswellknownthatinsulinisthemostimportantlipogenichormone.InsulinincreasesFASexpressionandactivityinhumansandinrodentadipocytesinprimaryculture(Moustaïdetal.1996,Claycombeetal1998).Evidencessuggestthattheregulationoflipogenicgenesexpressionbyin-sulinismediatedbysterolresponsiveelementbindingprotein1c(SREBP-1c)(Denechaudetal.2008b).LIPOLYSISANDTRIACYLGLYCEROLFATTYACIDCYCLINGAdiposetissueisconsideredasthebody'slargeststor-ageorganforenergyintheformoftriacylglycerols,whicharemobilizedthroughlipolysispathwaytopro-videfueltootherorgans.Releaseofnon-esteriedfattyacids(NEFA)isaspecicfunctionfortheadiposetissue;infact,noothertissueinthemammalianbodyisknowntomobilizeNEFAandreleasethemtothecirculationtobetakenupbyothertissues.Therstevidenceofalipolyticenzymesensitivetohormone,inadiposetissuewithdifferentcharacteristicofLPL,wasobservedinthe1960sdecade.Itwasver-iedthatthisenzymewasstimulatedbyadrenalinandadrenocorticotrophichormoneandinhibitedbyinsulin(Hollenbergetal.1961,BjörntorpandFurman1962,RodbellandJones1966,GoodridgeandBall1965).Vaughanetal.(1964)denominatedthisenzymeasahormone-sensitivelipase(HSL).TheHSLexistsintwoforms:anactivephosphory-latedformandaninactive(orlessactive)non-phospho-rylatedform,andthisinterconversionisregulatedbyhormonalaction(SträlforsandHonnor1989).Phospho-rylationofHSLresultsinincreasedhydrolyticactivity,translocationofHSLfromcytosoltothelipiddropletsurface,andenhancedTAGbreakdowninthecell.ThehydrolyticactionofHSLisregulatedbyperilipinA,alipiddroplet-associatedprotein.PhosphorylationofperilipinbycAMP-dependentproteinkinase(PKA)fa-cilitatethetranslocationofHSLtothelipiddroplet(CarmenandVíctor2006).OpposingregulationoflipolysisinWATbycate-cholaminesandinsulinhasbeenwelldocumented.Dur-ingfastingorexercise,catecholaminesarethemajorhor-monestostimulatelipolysis.Hormonebindingtoadren-ergicreceptors(-adrenergic)andstimulatingadenylatecyclaseactivityleadstoanincreaseinintracellularcAMPconcentrationsactivatingPKA.Inthefedstate,insulininhibitslipolysisbydephosphorylationofHSLandac-tivationofphosphodiesterasethatreducescAMPlevels(Jaworskietal.2007).Alongwithinsulinandcatecholamines,lipolysisisstimulated,undertightregulation,bycatecholami-nes,glucagon,adrenocorticotrophichormone(ACTH),growthhormone,testosterone,atrialnatriureticpeptideandleptin(Slavinetal.1994,Steinbergetal.2002,Sengenesetal.2002).Autocrine/paracrinefactorsmayalsoparticipateinthepreciseregulationoflipolysisinadipocytestomeetthephysiologicandmetabolicchanges.NEFAcanalsobeoxidizedorusedforreesteri-cationinadipocytestoproduceTAG.HighratesofFAre-estericationinTAGhavebeenshowntooccurinWATduringfasting,bothinratsandhumans(Reshefetal.2003).EstericationofFAsrequiresglycerol3-phosphateformationwhich,underlipolyticsituations,doesnotarisefromglycolysissinceglucoseutilizationisstronglyreducedundersuchcircumstances.In1967,Ballardetal.rstlydemonstratedtheac-tivityofphosphoenolpyruvatecarboxykinase(PEPCK)andtheglycerol3-phosphatesynthesisfrompyruvateinwhiteadiposetissue.In1969,thispathwaywasnamedglyceroneogenesisbyGorinetal.,Olswangetal.(2002)reportedthataselectiveablationofPEPCKexpressioninWATofhomozygousmutantmicecausedareductionontriglyceridedeposition,with25%oftheanimalsdis-playinglipodystrophy.Theseresultsdemonstratedthephysiologicalroleofglyceroneogenesistomaintainfathomeostasisinadiposetissue.Aminoacids,lactateandpyruvatecouldbeutilizedasasubstratetodenovoglyc-erol3-phosphatesynthesis.Ithasbeenshownthatratstreatedwithhyperproteiccarbohydratefreediethaveanincreaseinthewhiteadiposetissueglyceroneogenesis(Botionetal.1995).AnAcadBrasCienc(2009)81(3) main2009/7/2714:26page456#4 456CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAEFFECTOFDIETARYFATONWHITEADIPOSETISSUEMETABOLISMTheprevalenceofobesityisincreasingworldwide,anddatafromtheliteratureindicatethatenvironmentalandbehavioralaspectsplayanimportantcausalrole.Amongtheenvironmentalinuences,thepercentageoffaten-ergyintheeverydaydietandthelackofphysicalactivityaretwoimportantfactors(Jéquier2002).Obesityisoftenaccompaniedbyabnormalitiesincarbohydrateandlipidmetabolismandininsulinandleptinsecretionandaction(Buettneretal.2000,Zhouetal.1998).Exposuretohigh-fatdietsforprolongedperiodsresultsinpositiveenergybalanceandobesityincertainrodentmodelsthatcanbeconsideredanad-equatemodelofhumanobesity(Gaívaetal.2001,Linetal.2000a).Thehyperlipidicdietinducedamorepro-nouncedbodyweightgainaccompaniedbyanincreaseintheadiposity,carcasslipogenesisrateandserumtria-cylglycerols,regardlessoftheregimenofadministra-tion,i.e.,eithercontinuousorcycledwithchow(Esta-dellaetal.2004).Ithasbeenshownthatdieteticmanipulations,hormones,andcytokinesinducedistinctmetabolicre-sponsesatdifferentfatdepots(Pond1999).High-fatdietsreducedtheactivityoflipogenicenzymesandli-pogenesisrateinretroperitonealandinguinalfatdepots(Gaívaetal.2001,Rothwelletal.1983),butincreasedlipoproteinlipaseactivityinvisceralfat(Robertsetal.2002).ThetypeofdietaryfathasbeenshowntoinuencehepaticandWATmetabolism.Althoughitiswelldocu-mentedthattheconsumptionofhigh-fatdietscaninduceobesity,theimpactofdietaryfattyacidcompositiononadiposetissuelipidmetabolismhasbeenexaminedbysomeauthors,withconictingresults.Wehavepreviouslyshownthatfeedingyoungratsfor8weeksondietscontainingeithern-6polyunsat-uratedfattyacid(PUFA)orlong-chainsaturatedfattyacids,as33%oftotalenergy,producedsimilareleva-tionsinbody-weightgainandcarcassfatcontent(daSilvaetal.1996).SimilarresultswereobtainedbyAwadetal.(1990).Incontrast,Shimomuraetal.(1990)reportedthatasafoweroildietproducedalowerbody-fatgaininyoungratsthanatallowdiet,bothat45%oftotalenergy.However,ratsthatwerefedwithamaizeoildietfor9monthswereheavierandfatterthanthosethatreceivedalarddiet(Hilletal.1993).Then-3PUFAfoundinshoilshavereceivedconsiderableinterest,sincetheyhavebeenshowntoexertbenecialhealthef-fects(Calder1998).Tsuboyama-Kasaokaetal.(1999)havedemonstratedthatmicereceiving60%ofdietaryenergyasn-3fattyacids,during5months,didnotde-velopobesity.Contrarily,ashoildietelevatedbodyfatandloweredbodyproteincontent,comparedwithasaf-oweroildiet(Dullooetal.1995),whilenodifferenceinbody-weightgainwasobservedbetweenratswhichwerefedwithlardorann-3fattyacid-supplementedlarddiet(Rustanetal.1993).Noeffectonlipolysisandlipogenesisrateswasre-portedbyAwadetal.(1990)whencomparingn-6PUFA,n-3PUFAandsaturateddiets,whileFickovaetal.(1998)foundhighernoradrenaline-stimulatedlipolysisinratswhichwerefedwithn-3PUFAthaninthosewithn-6PUFA.Ontheotherhand,wehaveshownthatratsthatwerefedwithn-3PUFAorn-3plusn-6PUFAdietshadalowerWATlipolysisrateascomparedtocontroldiet(Gaívaetal.2001).ThereductionofWATlipoly-sisratebyn-3PUFAhasbeenshownbyothers(Singeretal.1990,Dagnelieetal.1994).Thisobservationisconsistentwiththereportedshoil-inducedreductioninplasmafreefattyacids(Ottoetal.1992)andeleva-tionofinsulinsensitivity(Hilletal.1993).Dietsenrichedwithn-6PUFAhavebeenshowntodecreaseFASmRNAinliverandWATand,thus,lipoge-nesiscapacityinrats(Tsuboyama-Kasaokaetal.1999).Fernández-Quintelaetal.(2007)postulatedthatsuppressionoflipogenicenzymegeneexpressionin-ducedbyPUFAisrelatedtochangesintheexpres-sionandnuclearlocalizationofthetranscriptionfactor,sterol-regulatoryelement-bindingprotein-1(SREBP-1),ratherthantoadirecteffectonperoxisomeprolifera-tor-activatedreceptorsPPARs,afamilyoftranscriptionfactorsthatregulateenergybalancebypromotingeitherenergydepositionorenergydissipation.RegionaldifferencesinthesensitivityofWATde-potstodietarymanipulationshavebeenfound(Belzungetal.1993).Wealsoobservedsomedifferencesbe-tweenretroperitonealandepididymalWATmetabolicre-sponsestothefattydiets.Dietenrichedwithsoyabeanoil(richinPUFAn-6)signicantlyincreasedretroperi-AnAcadBrasCienc(2009)81(3) main2009/7/2714:26page457#5 DIETARYFATANDWHITEADIPOSETISSUE457tonealWATweightand14C-labelledlipidaccumulation,whilethesamevariableswereaffectedinepididymalWATbydietenrichedwithshoil(richinPUFAn-3andsaturatedfattyacid).AllPUFA-richdietsincreasedthelipogenesisdenovorate(Gaívaetal.2001).In-creasedretroperitonealWATlipogenesisrateaftern-3-andn-6-richdietshasbeenreportedpreviously(RaclotandGroscolas1994,Fickovaetal.1998).Theconsumptionofindustrializedfoodhasledtoanincreasedintakeofhydrogenatedvegetableoils,whichhavesubstantialamountsofsaturatedandtrans-fattyacids(TFAs)(Allisonetal.1999,Popkin1998).Recently,wehaveshownthattheingestionofTFAduringgestationandlactationincreasesthecarcasslipidcontentin21-day-oldand90-day-oldoffspring(Pisanietal.2008a,b).SimilarndingsweredescribedbyTakeuchietal.(1995)inanimalstreatedwithadietrichinsaturatedfattyacids.Furthermore,ShillabeerandLau(1994)demonstratedthatdietsrichinsaturatedfattyacidspromotethereplicationofadipocytes.ItispossiblethatthismechanismhascontributedtothehighcarcasslipidcontentfoundintheTFAfeedinggroups.Silvaetal.(2006),studyingtheeffectsofTFAin-gestionjustduringlactation,veriedincreasedlipogen-esisdenovoratesandlipidcontentsintheepididymalWATofoffspringaged45days.Thesamestudyob-servedmoremonounsaturatedandsaturatedfattyacidsintheWAToftheTFA-exposedoffspring.BecausethosefattyacidshavebeenshowntobemobilizedatalowerratethanPUFA(Raclot2003),adecreasedlipo-lysisratecouldalsobepresentintheTFA-exposedrats.SECRETORYFUNCTIONOFWHITEADIPOSETISSUEObesityisassociatedwithachroniclowgradeinam-mation,andithasbeensuggestedthatinammationmaybethelinkbetweenobesity,type2diabetesandcardio-vasculardisease(Bulloetal.2003).Inthisregard,ithasrecentlybeendemonstratedthatdiabetesisassociatedwithraisedinammation-sensitiveplasmaproteinlevelsinoverweightandobesemen,butnotinmenofnormalweight(Engstrometal.2003).Cardiovascularandmetabolicdiseasesareassoci-atedwithobesityandwithalterationsintheproductionofadipokynes,e.g.,leptin,resistin,adiponectin,TNF-,plasminogenactivatorinhibitor-1(PAI-1)andhap-toglobin(TrayhurnandBeattie2001,Friedrichsetal.1995,Nascimentoetal.2004).Asstatedbefore,thisreviewfocusesonhapto-globin,TNF-,plasminogenactivatorinhibitor-1andadiponectin.Theliverisregardedasthemainsiteofthesyn-thesisofhaptoglobin,asofotheracutephaseproteins.HepaticexpressionofthehaptoglobingeneisregulatedbyIL-1,IL-6,glucocorticoidsandTNF-inthecaseofrodents,butmainlybyIL-6anddexamethasoneinhu-mans(Baumannetal.1990,Mackiewiczetal.1991).IL-6is,however,thecommoninammatorycytokinemediatorforhaptoglobingeneregulationintheliverofallstudiedspecies(Pajovicetal.1994).Theidenticationofhaptoglobin,inparticular,asaputativesecretedfactorfromWAT(Friedrichsetal.1995,Kratchmarovaetal.2002,Chiellinietal.2002)isconsistentwiththeconceptthatobesityanddiabetesarestatesofchronicmildinammation.ExpressionofthehaptoglobingeneinepididymalWATwasrstre-portedinnormalmice,withincreasesinexpressionbe-ingobservedfollowinginductionofaninammatoryre-sponsewithlipopolysaccharide(Friedrichsetal.1995).ThelevelofhaptoglobinmRNAhasbeenshowntobeelevatedinWATofseveralobesemodels,includingob/obanddb/dbmice(Chiellinietal.2002).Wehavedemonstratedthatthegeneencodingtheacutephasereactanthaptoglobinishigherinepididy-malWATfromobese(ob/ob)micerelativetotheirleansiblings,andalsohaptoglobinisexpressedineachofthemainWATdepotsofmice,bothinternalandsubcu-taneous,aswellasininterscapularbrownadiposetis-sue.Haptoglobinexpressionoccursintheadipocytesthemselvesratherthaninthecellsofthestromal-vascularfraction(Nascimentoetal.2004).Theincreasedhaptoglobinexpressionintheepi-didymalWATofobeseanimalssuggeststhatWATcouldbeasourceoftheincreaseinplasmahaptoglobinlevelobservedinobesesubjects(Engstrometal.2003,Scribaetal.1979).IncreasedproductionofthisacutephasereactantbyWATintheobesestatecouldcontributetothemildinammationthataccompaniesobesity.Haptoglobinisatetramericglycoproteinwhichbindshaemoglobin,preventingbothironlossandkid-neydamageduringhaemolysis.IthasanantioxidantAnAcadBrasCienc(2009)81(3) main2009/7/2714:26page458#6 458CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAfunctionandhasbeenreportedtobeangiogenic,stimu-latingendothelialcelldifferentiationandvascularisation(Cidetal.1993).Withinadiposetissue,haptoglobincouldplayaroleasanantioxidantorinangiogenesis.Alternatively,haptoglobinsynthesizedinthetissuemaynothavealocalrolebutinsteadmaycontributeprimar-ilytothecirculatingpooloftheproteinandthegeneralinammatoryresponse.In3T3-L1adipocytes,haptoglobinmRNAwasre-ducedbythePPAR agonist,rosiglitazone.Incon-trast,itwasstimulatedbydexamethasone,IL-6,TNF-,andLPS(Nascimentoetal.2004).Ininvivostud-ies,Friedrichsetal.(1995)foundthattheinjectionofLPSinmiceresultedinaseveralfoldincreaseinhap-toglobinmRNAlevelinadiposetissue.SinceLPSre-ceptors(Toll-likereceptor)arepresentinwhiteadiposetissue(Linetal.2000b),theeffectoftheinamma-toryagentonhaptoglobinexpressioninthetissueinvivomayreect,atleastinpart,adirectinteractionwiththeadipocyte.ThemostpowerfuleffectonhaptoglobingeneexpressioninourstudywaswiththeadditionofTNF-.TNF-alsostimulatestheproductionofotheradi-pokines,suchasleptin.EarlierstudieshaveshownthatTNF-increasesbothleptingeneexpressionandleptinsecretioninWATandin3T3-L1adipocytes,whileleptinmRNAlevelshavebeenreportedtobelowerinTNF-decientmice(Kirchgessneretal.1997,Faggionietal.1998,LanghansandHrupka1999).Moreover,WATexpressionofTNF-alsoappearstoberelatedtothecirculatinglevelofotherinammatorymarkers,suchasC-reactiveprotein,brinogen,alkalinephosphataseandalbumin.TNF-hasbeenassociatedwithobesity-relatedtype2diabetes.ThiswasrstdemonstratedbyHotamis-ligiletal.(1996).TheyshowedthatTNF-iselevatedinWATfromobesediabeticrodentsanditisamediatorofobesity-relatedinsulinresistanceandtype2diabetes.Evidencesfromliteratureclearlyestablishedacor-relationbetweenTNF-andinsulinresistanceinrodents(Ventreetal.1997,Uysaletal.1997).However,therearedisagreementsabouttheroleofTNF-ininsulinresistanceinhumans;someresearchersdonotndas-sociationamongthem(Rushetal.2007,Zavaronietal.2003),whileothersdo(Behreetal.2005,Hivertetal.2008).Initially,adipocyteswereconsideredthepredom-inantsourceofadiposetissueTNF-.However,re-centstudieshavedemonstratedthatpreadipocytes,en-dothelialcells,smoothmusclecells,broblasts,leuko-cytesandmacrophages,whicharepresentinWATasastromavascularfraction,canproducesubstantiallymoreTNF-thanadipocytes(Fainetal.2004,Weisbergetal.2003).ItiswellknownthatobesityisassociatedwithanincreasedinltrationofmacrophagesintoWAT(Coenenetal.2007,CawthornandSethi2008),especiallyinvis-ceralfatpad,whichmayparticipateintheinammatoryreactionthatlinkscentraladipositytoinsulinresistance(Curatetal.2006).ThemolecularmechanismforTNF--inducedin-sulinresistanceinvolvesexcessivephosphorylationofextracellularsignal-regulatedkinase-1/2(ERK-1/2)andc-JunNH2-terminalkinase(JNK),concomitantwithin-creasedserineandreducedtyrosinephosphorylationofinsulinreceptorsubstrate-1(IRS-1),andalsoTNF--inducedtranscriptionfactor,NF-k(CawthornandSethi2008).TNF-upregulatesPAI-1expressioninadipocytesandWAT,whichislikelytocontributetoobesityas-sociatedwithcardiovascularcomplicationsofmetabolicsyndrome.Plasminogenactivatorinhibitor-1(PAI-1)hastraditionallybeenlinkedtothepathogenesisofatheros-clerosis,althoughevidencesuggeststhatitisalsoin-volvedinthedevelopmentofobesityandinsulinresis-tance(Maetal.2004).PlasmaPAI-1isderivedfromseveralsources,in-cludingthevascularendothelium,WATandliver(DeTaeyeetal.2005).Eventhough,WATisasiteofabun-dantPAI-1synthesis(Allessietal.1997,SawdeyandLoskutoff1991).PAI-1isaprocoagulativeagentandbrinolysisin-hibitor.Therefore,highcirculatingplasmaPAI-1con-centrationisastrongriskfactorofthromboticdiseaseandindependentpredictorofcoronaryarterydisease(Segarraetal.2001).Severalstudiesshowedthatadi-posevisceraltissuemassinhumanswaspositivelycor-relatedwithplasmaPAI-1concentration(Cigolinietal.1996,Regaetal.2005).Recently,Sakamotoetal.(2008)showedthatin-sulinandtriacylglycerols,incombinationwithhighconcentrationofinsulin,enhancedPAI-1productionbutAnAcadBrasCienc(2009)81(3) main2009/7/2714:26page459#7 DIETARYFATANDWHITEADIPOSETISSUE459decreasedadiponectinproductionbyadipocytes.Thesetwoadipokineshaveopposingeffectsonthepathogene-sisofcoronaryarterydisease.AdiponectinisthetranscriptionalproductoftheapM1geneandisthemostabundantlysecretedpro-teinfromadiposetissueinhumans(Maedaetal.1996,Aritaetal.1999).Transcriptionalregulationoftheadi-ponectingeneinvolvesanumberoftranscriptionfac-tors.Theadiponectinpromoterscontainbindingsitesforsterolregulatoryelements(SREs),peroxisomepro-liferator-activatedreceptor(PPAR)-responseelements,C/EBPsites,andE-boxes(Seoetal.2004).Recently,ithasbeenshownthatId3,theinhibitorofdifferentiationofthefamilyofproteins,inhibitsSREBP-1c-mediatedadiponectinpromoteractivation(Doranetal.2008).Thisadipokineincreasesinsulinsensitivityandhasanti-inammatoryandantiatherogeniceffects(DiezandIglesias2003).Decreasedserumadiponectinlevelshavebeenobservedinsubjectswithinsulinresistance,obesity,type2diabetesandheartdisease(DiezandIgle-sias2003,Hottaetal.2000).Serumadiponectinlevelsareinverselycorrelatedwithbodymassindex,centraladiposity,bloodpressure,fastingglycemia,insulinre-sistance,seruminsulinlevelsanduricacidlevels(Ya-mamotoetal.2002).Ithasbeendemonstratedthatadiponectinreduceshepaticproductionofglucoseandtheconcentrationoftriacylglycerolsinthemuscles,thusamelioratinginsulinsensitivity(Prins2002).Salmenniemietal.(2005)veriedthathypoadi-ponectinemiaisrelatedtoseveralfeaturesofmetabolicsyndrome(increasedfastingglycemia,triglyceridemia,centralobesityanddecreasedHDLcholesterol)andtohighlevelsofinammatorycytokines(IL-6,IL-1,andC-reactiveprotein).EFFECTOFDIETARYFATONWHITEADIPOSETISSUESECRETORYFUNCTIONOverthepastfewdecades,epidemiologicalandclinicalstudieshaveindicatedmanyrelationsbetweennutritionandhealth.Inthelastdecade,studieshaveestablishedthatdietarysignalscouldinuencegeneandproteinex-pression,whichfurthermodulatesmarkersofinamma-tionbyproducingbothpositiveandnegativeeffectsde-pendingonthenetchangesingeneexpression.Studieshaveprovedthattheincidenceofinsulinresistanceandheartdiseaseispositivelyrelatedtotheingestionofsaturatedfattyacids,andnegativelyrelatedtotheingestionofPUFA(Hu2003,SacksandKatan2002).High-fatdietsreportedlyimpairglucosemetabol-ism,stimulateabnormalglucoseproduction,causehy-perinsulinemiaandinsulinresistance(Reaven1988).Recently,Tsukumoetal.(2007)showedthatC3H/HeJmice,whichhavealoss-of-functionmutationinToll-likereceptor4(TLR4),areprotectedagainstthedevelop-mentofobesityandinsulinresistanceinducedbyhighfattydietaccompaniedbyalesspronouncedincreaseinadipocytesizethanthewildmice.TLR2andTLR4areexpressedinadiposetissueandothertissues(e.g.macrophages,andmuscle),andplayacriticalroleininducinginnateimmuneresponsesinmammals.TLR4isactivatedbylipopolysaccharideandsaturatedfattyacids,whichareinducersofinsulinresistance.Sincethat,Tsukumoetal.(2007)suggestedthatTLR4maybeacandidateforparticipationininsulinresistanceinducedbysaturatedfattyacidrichdiet.Ithasbeenobservedthatsaturatedfattyacidscandirectlyinteractwiththeimmunemodulationandin-ammationresponsethroughtheactivationofTLRsinmacrophages(Leeetal.2001).TLRisalsoexpressedin3T3-L1cells,mouseculturedadipocytesandmouseandhumanWAT(Shietal.2006,Creelyetal.2007).Thisreinforcesthendingsinwhichinammationandthecompositionoffattyacidsinthediet,particularlydi-etsrichinsaturatedfat,arecloselyrelatedtometabolicdisorders.Wehaveshownthatlardenricheddietingestion,for2or60days,increasedhaptoglobingeneexpressioninmiceWAT.Itwasalsofoundthat3T3-L1adipocyterespondstopalmiticacidinadosedependentmanner,inwhichthehaptoglobingeneexpressionisincreasedindoseshigherthan100M(Oyamaetal.2005).TreatmentwithpalmitateinducestheNF-kandtheexpressionofIL-6andTNF-mRNAin3T3-L1adipocytes(AjuwonandSpurlock2005).InvivostudyshowedthatWATTNF-geneexpressionwassigni-cantlyincreasedbythecafeteriadiet,richinsaturatedfattyacid,whileeicosapentaenoicacid(EPA)treatmentwasabletopreventtheriseinthisinammatorycytokine(Pérez-Matuteetal.2007).AnAcadBrasCienc(2009)81(3) 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460CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAIbrahimetal.(2005)demonstratedthattreatmentwithTFAhasamuchgreatereffectindecreasingadipo-cyteinsulinsensitivitythantreatmentwithsaturatedfattyacids.Recently,wehaveshownthatmaternalingestionofhydrogenatedvegetablefatrichinTFAs,duringges-tationandlactation,alteredthebloodlipidprolesanddecreasedserumadiponectinlevel,togetherwithade-creaseinadiponectinmRNAandanincreaseinTNF-andPAI-1mRNAlevelsintheWAToftheir21-day-oldoffspring(Pisanietal.2008b).Wealsohavefoundanincreasedlevelsofinsulin,adiponectin,bodyfatandepi-didymalWATPAI-1mRNAin90-day-oldoffspringofratswhichwerefedwithadietcontainingTFAduringgestationandlactation(Pisanietal.2008a).Thesere-sultssuggestedthatearlyexposuretoTFAcausedanincreaseinWATPAI-1geneexpressionandthatthisalterationbecameprogrammed.Long-termdiet-fedratsorshort-termdiet-fedrats(2days)withfat-enriched,glucose-enricheddietshowedloweradiponectinmRNAinepididymalWATandplasmaconcentration,accompaniedbyanincreaseinplasmatriacyglycerolandNEFAlevels(Naderalietal.2003).WehaveshownthatadiponectingeneexpressionwaslowerinretroperitonealWATafteracutetreatment(2days)withdietsenrichedwithsoybean,coconutandshoils,orlard.Thesamereductioninlevelsofadipo-nectingeneexpressionwasobservedinepididymalWATofanimalschronically(60days)fedonlywithsoy-beanandcoconutdietsandin3T3-L1adipocytestreatedwithpalmitic,linoleic,EPAacids.Moreover,inthepresentstudy,adiponectingeneexpressioninsubcuta-neousWATwaslessaffectedbythehigh-fatdietthanintheretroperitonealandepididymaldepots.Acutetreat-mentwithhigh-fatdietsdecreasedtheserumadiponectinlevelsinallgroups,althoughshoildietdidnotaffectserumadiponectinconcentration,incontrasttotheotherhigh-fatdietchronictreatments(Buenoetal.2008).IthaspreviouslybeendescribedthatEPAincreasedserumadiponectinlevelsbutdidnotalteradiponectingeneexpression,eitherinsubcutaneous,dorsolumbar,orepididymalfatpads,inmicetreatedwithhigh-fatdiet(Flachsetal.2006).Inanotherstudy,db/dbmicetreatedwithn-6andn-3PUFA-enricheddiethadsimilarserumadiponectinlevelsandgonadalWATadiponectingeneexpression,ascomparedtoanimalstreatedwithalow-fatdiet(Todoricetal.2006).Recently,itwasreportedthatmicetreatedwithashoil-enricheddiethadincreasedserumadiponectinlevelsandraisedadiponectingeneexpressioninretroperitonealbutnotinepididymalWAT,comparedtoanimalswhichwerefedwiththecontroldietorsunoweroil(richinn-6PUFA)diet(Neschenetal.2006).Thedifferencesamongtheseresultsmaybepartlyexplainedbythedurationoftreatmentandthedietcomposition,suggestingthattheamountofn-3PUFAinthedietmightbeanimportantfactorforthestimula-tionofadiponectingeneexpression.CONCLUSIONThepresentreviewshowedthat,dependingontheout-comebeinganalyzed,thedurationoftheexposuretothehigh-fatfeeding,amountoffattyacidpresentinthedietandthetypeoffattyacidmayormaynothaveasignif-icanteffectonadiposetissuemetabolism.However,thelong-termorshort-term-highfatdiets,especiallyrichinsaturatedfattyacids,stimulatedtheexpressionofpro-inammatoryadipokinesandinhibittheexpressionofadiponectin,ananti-inammatoryadipokine.ACKNOWLEDGMENTSTheauthorsthankFundaçãodeAmparoàPesquisadoEstadodeSãoPaulo(FAPESP),ConselhoNacionaldeDesenvolvimentoCientícoeTecnológico(CNPq),Co-ordenaçãodeAperfeiçoamentodePessoaldeNívelSu-perior(CAPES)andFundodeAuxílioaosDocenteseAlunos(FADAUNIFESP).RESUMOAproximadamente40%dototaldeenergiaconsumidapelapopulaçãoocidentalérepresentadapeloslipídios,amaioriadelasendoingeridanaformadetriglicerídeosefosfolipídios.Ofocodestarevisãofoianalisaroefeitodostiposdegorduradadietasobreometabolismoefunçãosecretoradotecidoadi-posobranco,principalmente,sobreasecreçãodehaptoglobina,TNF-,inibidordoativadordeplasminogênio-1eadiponec-tina.Estudospréviosdemonstraramqueduranteaexposiçãodedietashiperlipídicas,aquantidadeeotipodeácidosgraxospresentesnadietapodemounãoterumefeitosignicanteAnAcadBrasCienc(2009)81(3) 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