AnaisdaAcademiaBrasileiradeCi - PDF document

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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,amountoffattyacidpresentinthedietandthetypeoffattyacidmayormaynothaveasignicanteffectonadiposetissuemetabolism.However,thelong-termorshort-termhighfatdiets,especiallyrichinsaturatedfattyacids,probablybyactivationoftoll-likereceptors,stimulatedtheexpressionofproinammatoryadipokinesandinhibitedadiponectinexpression.Furtherstudiesareneededtoinvestigatethecellularmechanismsbywhichdietaryfattyacidsaffectwhiteadiposetissuemetabolismandsecretoryfunctions.Keywords:adipokines,highfatdiets,metabolism,whiteadiposetissue.INTRODUCTIONWhiteadiposetissue(WAT)playsaroleinenergystor-ageandinsulationfromenvironmentaltemperatureandtrauma.Paleontologicalevidenceindicatesthattherapidbrainevolution,observedwiththeemergenceofHomoerectusatapproximately1.6–1.8millionyearsago,waslikelyassociatedwithincreasedbodyfatnessaswellasdietquality(Leonardetal.2003).Inthelongrun,whitefatmassreectsthenetbalancebetweenenergyexpen-ditureandenergyintake.Fatstorageoccursbothbythedirectuptakeofcirculatinglipoproteintriacylglyc-erols,whicharehydrolyzedbylipoproteinlipasetonon-esteriedfreefattyacids,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) 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454CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAThisreviewanalysestheimpactofdietaryfattyacidcompositiononadiposemetabolismandsecretoryfunction.METABOLISMOFWHITEADIPOSETISSUELIPOPROTEINLIPASEANDTRIACYLGLYCEROLMETABOLISMLipoproteinlipase(LPL)hasitsphysiologicalsiteofac-tionattheluminalsurfaceofcapillaryendothelialcells,wheretheenzymehydrolysesthetriacylglycerol(TAG)componentofcirculatinglipoproteinparticles,chylomi-cronsandverylowdensitylipoproteinstoprovidefreefattyacidsand2-monoacylglycerolfortissueutilization.LPLisdistributedinwiderangeoftissues(Cryer1981).Mostoftheplasmatriacylglycerolsareprovidedbydietarylipids,secretedfromtheintestineintheformofchylomicronorfromtheliverintheformofVLDL.Releasedintocirculationasnon-esteriedfattyacidsbylipoproteinlipase,thosearetakenupbyWATviaspecicplasmafattyacidtransporters(CD36,FATP,FABPpm)andusedfortriacylglycerolsynthesis(Largeetal.2004).LPLactivitycanbealteredinatissue-specicman-ner,whichisphysiologicallyimportantbecauseitdi-rectsfattyacidutilization,accordingtothemetabolicdemands,ofindividualtissues,sothatthedegradationoftriacylglycerol-richlipoproteinscanbetargetedtospe-cicsites.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,whichisalsomodiedinpathologicalconditionse.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) 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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-esteriedfattyacids(NEFA)isaspecicfunctionfortheadiposetissue;infact,noothertissueinthemammalianbodyisknowntomobilizeNEFAandreleasethemtothecirculationtobetakenupbyothertissues.Therstevidenceofalipolyticenzymesensitivetohormone,inadiposetissuewithdifferentcharacteristicofLPL,wasobservedinthe1960’sdecade.Itwasver-iedthatthisenzymewasstimulatedbyadrenalinandadrenocorticotrophichormoneandinhibitedbyinsulin(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-estericationinTAGhavebeenshowntooccurinWATduringfasting,bothinratsandhumans(Reshefetal.2003).EstericationofFAsrequiresglycerol3-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) 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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-3PUFAfoundinshoilshavereceivedconsiderableinterest,sincetheyhavebeenshowntoexertbenecialhealthef-fects(Calder1998).Tsuboyama-Kasaokaetal.(1999)havedemonstratedthatmicereceiving60%ofdietaryenergyasn-3fattyacids,during5months,didnotde-velopobesity.Contrarily,ashoildietelevatedbodyfatandloweredbodyproteincontent,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).Thisobservationisconsistentwiththereportedshoil-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)signicantlyincreasedretroperi-AnAcadBrasCienc(2009)81(3) 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DIETARYFATANDWHITEADIPOSETISSUE457tonealWATweightand14C-labelledlipidaccumulation,whilethesamevariableswereaffectedinepididymalWATbydietenrichedwithshoil(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).SimilarndingsweredescribedbyTakeuchietal.(1995)inanimalstreatedwithadietrichinsaturatedfattyacids.Furthermore,ShillabeerandLau(1994)demonstratedthatdietsrichinsaturatedfattyacidspromotethereplicationofadipocytes.ItispossiblethatthismechanismhascontributedtothehighcarcasslipidcontentfoundintheTFAfeedinggroups.Silvaetal.(2006),studyingtheeffectsofTFAin-gestionjustduringlactation,veriedincreasedlipogen-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).Theidenticationofhaptoglobin,inparticular,asaputativesecretedfactorfromWAT(Friedrichsetal.1995,Kratchmarovaetal.2002,Chiellinietal.2002)isconsistentwiththeconceptthatobesityanddiabetesarestatesofchronicmildinammation.ExpressionofthehaptoglobingeneinepididymalWATwasrstre-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) “main”—2009/7/27—14:26—page458—#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-decientmice(Kirchgessneretal.1997,Faggionietal.1998,LanghansandHrupka1999).Moreover,WATexpressionofTNF-alsoappearstoberelatedtothecirculatinglevelofotherinammatorymarkers,suchasC-reactiveprotein,brinogen,alkalinephosphataseandalbumin.TNF-hasbeenassociatedwithobesity-relatedtype2diabetes.ThiswasrstdemonstratedbyHotamis-ligiletal.(1996).TheyshowedthatTNF-iselevatedinWATfromobesediabeticrodentsanditisamediatorofobesity-relatedinsulinresistanceandtype2diabetes.Evidencesfromliteratureclearlyestablishedacor-relationbetweenTNF-andinsulinresistanceinrodents(Ventreetal.1997,Uysaletal.1997).However,therearedisagreementsabouttheroleofTNF-ininsulinresistanceinhumans;someresearchersdonotndas-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).ItiswellknownthatobesityisassociatedwithanincreasedinltrationofmacrophagesintoWAT(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-1isaprocoagulativeagentandbrinolysisin-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) 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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)veriedthathypoadi-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).Thisreinforcesthendingsinwhichinammationandthecompositionoffattyacidsinthediet,particularlydi-etsrichinsaturatedfat,arecloselyrelatedtometabolicdisorders.Wehaveshownthatlardenricheddietingestion,for2or60days,increasedhaptoglobingeneexpressioninmiceWAT.Itwasalsofoundthat3T3-L1adipocyterespondstopalmiticacidinadosedependentmanner,inwhichthehaptoglobingeneexpressionisincreasedindoseshigherthan100M(Oyamaetal.2005).TreatmentwithpalmitateinducestheNF-kandtheexpressionofIL-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,alteredthebloodlipidprolesanddecreasedserumadiponectinlevel,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,coconutandshoils,orlard.Thesamereductioninlevelsofadipo-nectingeneexpressionwasobservedinepididymalWATofanimalschronically(60days)fedonlywithsoy-beanandcoconutdietsandin3T3-L1adipocytestreatedwithpalmitic,linoleic,EPAacids.Moreover,inthepresentstudy,adiponectingeneexpressioninsubcuta-neousWATwaslessaffectedbythehigh-fatdietthanintheretroperitonealandepididymaldepots.Acutetreat-mentwithhigh-fatdietsdecreasedtheserumadiponectinlevelsinallgroups,althoughshoildietdidnotaffectserumadiponectinconcentration,incontrasttotheotherhigh-fatdietchronictreatments(Buenoetal.2008).IthaspreviouslybeendescribedthatEPAincreasedserumadiponectinlevelsbutdidnotalteradiponectingeneexpression,eitherinsubcutaneous,dorsolumbar,orepididymalfatpads,inmicetreatedwithhigh-fatdiet(Flachsetal.2006).Inanotherstudy,db/dbmicetreatedwithn-6andn-3PUFA-enricheddiethadsimilarserumadiponectinlevelsandgonadalWATadiponectingeneexpression,ascomparedtoanimalstreatedwithalow-fatdiet(Todoricetal.2006).Recently,itwasreportedthatmicetreatedwithashoil-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),ConselhoNacionaldeDesenvolvimentoCientícoeTecnológico(CNPq),Co-ordenaçãodeAperfeiçoamentodePessoaldeNívelSu-perior(CAPES)andFundodeAuxílioaosDocenteseAlunos(FADA–UNIFESP).RESUMOAproximadamente40%dototaldeenergiaconsumidapelapopulaçãoocidentalérepresentadapeloslipídios,amaioriadelasendoingeridanaformadetriglicerídeosefosfolipídios.Ofocodestarevisãofoianalisaroefeitodostiposdegorduradadietasobreometabolismoefunçãosecretoradotecidoadi-posobranco,principalmente,sobreasecreçãodehaptoglobina,TNF-,inibidordoativadordeplasminogênio-1eadiponec-tina.Estudospréviosdemonstraramqueduranteaexposiçãodedietashiperlipídicas,aquantidadeeotipodeácidosgraxospresentesnadietapodemounãoterumefeitosignicanteAnAcadBrasCienc(2009)81(3) 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DIETARYFATANDWHITEADIPOSETISSUE461sobreometabolismodotecidoadiposo.Entretanto,otrata-mentoacurtooulongoprazocomdietahiperlipídica,espe-cialmentericaemácidosgraxossaturados,provavelmenteporativarreceptorestoll-like,estimulaaexpressãodeadipocinaspró-inamatóriaseinibeaexpressãodeadiponectina.Estu-dosadicionaissãonecessáriosparainvestigarosmecanismoscelularespelosquaisosácidosgraxosdadietaafetamafunçãosecretóriaemetabólicadotecidoadiposobranco.Palavras-chave:adipocinas,dietashiperlipídicas,metabolis-mo,tecidoadiposobranco.REFERENCESAJUWONKMANDSPURLOCKME.2005.Palmitateac-tivatestheNF-ktranscriptionfactorandinducesIL-6andTNF-expressionin3T3-L1adipocytes.JNutr135:1841–1846.ALLESSIMC,PEIRETTIF,MORANGEP,HENRYM,NALBONEGANDJUHAN-VAGUEI.1997.Productionofplasminogenactivatorinhibitor-1byhumanadiposetis-sue:possiblelinkbetweenvisceralfataccumulationandvasculardisease.Diabetes46:860–867.ALLISONDB,EGANSK,BARRAJLM,CAUGHMANC,INFANTEMANDHEIMBACHJT.1999.Estimatedin-takesoftransfattyandotherfattyacidsintheUSpopula-tion.JAmDietAssoc99:166–174.ARITAYETAL.1999.Paradoxicaldecreaseofanadipose-specicprotein,adiponectin,inobesity.BiochemBiophysResCommun257:79–83.AWADAB,BERNARDISLLANDFINKCS.1990.Failuretodemonstrateaneffectofdietaryfattyacidcomposi-tiononbodyweight,bodycompositionandparametersoflipidmetabolisminmaturerats.JNutr120:1277–1282.BALLARDFJ,HANSONRWANDLEVEILLEGA.1967.Phosphoenolpyruvatecarboxykinaseandthesynthesisofglyceride-glycerolfrompyruvateinadiposetissue.JBiolChem242:2746–2750.BAUMANNH,MORELLAKK,JAHREISGPANDMARIN-KOVICS.1990.Distinctregulationoftheinterleukin-1andinterleukin-6responseelementsoftherathaptoglobingeneinratandhumanhepatomacells.MolCellBiol10:5967–5976.BEHRECJ,FAGERBERGB,HULTENLMANDHULTHEJ.2005.ThereciprocalassociationofadipocytokineswithinsulinresistanceandC-reactiveproteininclinicallyhealthymen.Metabolism54:439–444.BELZUNGF,RACLOTTANDGROSCOLASR.1993.Fishoiln-3fattyacidsselectivelylimitthehypertrophyofab-dominalfatdepotsingrowingratsfedhigh-fatdiets.AmJPhysiol264:r1111–r1118.BJÖRNTORPPANDFURMANRH.1962.Lipolyticactivityinratepididymalfatpads.AmJPhysiol203:316–322.BOTIONLM,KETTELHUTICANDMIGLIORINIRH.1995.Increasedadiposetissueglyceroneogenesisinratsadaptedtoahighprotein,carbohydrate-freediet.HormMetabRes27:310–313.BRAUNJEANDSEVERSONDL.1992.Lipoproteinlipasere-leasefromcardiacmyocytesisincreasedbydecavanadatebutnotinsulin.AmJPhysiol262(5Pt1):E663–E670.BUENOAA,OYAMALM,ESTADELLAD,HABITANTECA,BERNARDESBS,RIBEIROEBANDOLLERDONASCI-MENTOCM.2005.Lipidmetabolismofmonosodiumglutamateobeseratsafterpartialremovalofadiposetis-sue.PhysiolRes54:57–65.BUENOAA,OYAMALM,DEOLIVEIRAC,PISANILP,RIBEIROEB,SILVEIRAVLANDOLLERDONASCI-MENTOCM.2008.Effectsofdifferentfattyacidsanddietarylipidsonadiponectingeneexpressionin3T3-L1cellsandC57BL/6Jmiceadiposetissue.PugersArch455:701–709.BUETTNERR,NEWGARDCB,RHODESCJANDO'DO-HERTYRM.2000.Correctionofdiet-inducedhyper-glycemia,hyperinsulinemia,andskeletalmuscleinsulinresistancebymoderatehyperleptinemia.AmJPhysiolEndocrinolMetab278:E563–E569.BULLOM,GARCIA-LORDAP,MEGIASIANDSALAS-SAL-VADOJ.2003.Systemicinammation,adiposetissuetu-mornecrosisfactor,andleptinexpression.ObesityRes11:525–531.CALDERPC.1998.Immunoregulatoryandanti-inammat-oryeffectsofn-3polyunsaturatedfattyacids.BrazJMedBiolRes31:467–490.CARMENGYANDVÍCTORSM.2006.Signallingmecha-nismsregulatinglipolysis.CellSignal18:401–408.CAWTHORNWPANDSETHIJK.2008.TNF-andadipocytebiology.FEBSLett582:117–131.CHIELLINICETAL.2002.ObesitymodulatestheexpressionofhaptoglobininthewhiteadiposetissueviaTNF-.JCellPhysiol190:251–258.CIDMC,GRANTDS,HOFFMANGS,AUERBACHR,FAUCIASANDKLEINMANHK.1993.Identicationofhap-toglobinasanangiogenicfactorinserafrompatientswithsystemicvasculitis.JClinInvest91:977–985.CIGOLINIM,TARGHERG,BERGAMOANDREISIA,TONOLIM,AGOSTINOGANDDESANDREG.1996.AnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:26—page462—#10 462CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAVisceralfataccumulationanditsrelationtoplasmahemo-staticfactorsinhealthymen.ArteriosclerThrombVascBiol16:368–374.CLAYCOMBEKJ,JONESBH,STANDRIDGEMK,GUOY,CHUNJT,TAYLORJWANDMOUSTAÏD-MOUSSAN.1998.Insulinincreasesfattyacidsynthasegenetranscrip-tioninhumanadipocytes.AmJPhysiol274:R1253–R1259.COENENKR,GRUENML,CHAITAANDHASTYAH.2007.Diet-inducedincreasesinadiposity,butnotplasmalipids,promotemacrophageinltrationintowhiteadiposetissue.Diabetes56:564–573.CREELYSJ,MCTERNANPG,KUSMINSKICM,FISHERM,DASILVANF,KHANOLKARM,EVANSM,HARTEALANDKUMARS.2007.Lipopolysaccharideactivatesaninnateimmunesystemresponseinhumanadiposetissueinobesityandtype2diabetes.AmJPhysiolEndocrinolMetab292:E740–E747.CRYERA.1981.Tissuelipoproteinlipaseactivityanditsactioninlipoproteinmetabolism.IntJBiochem13:525–541.CURATCA,WEGNERV,SENGENESC,MIRANVILLEA,TONUSC,BUSSERANDBOULOUMIEA.2006.Macro-phagesinhumanvisceraladiposetissue:increasedaccu-mulationinobesityandasourceofresistinandvisfatin.Diabetologia49:744–747.DASILVAMH,PITHONTCANDDONASCIMENTOCM.1996.Effectofsaturatedandpolyunsaturatedfattyacidsrichdietsonhepaticandadiposetissuelipidmetabolisminrats.IntJVitamNutrRes66:258–262.DAGNELIEPC,RIETVELDT,SWARTGR,STIJNENTANDVANDENBERGJW.1994.Effectofdietaryshoilonbloodlevelsoffreefattyacids,ketonebodiesandtriacyl-glycerolinhumansLipids29:41–45.DETAEYEB,SMITHLHANDVAUGHANDE.2005.Plas-minogenactivatorinhibitor-1:acommondenominatorinobesity,diabetesandcardiovasculardisease.CurrOpinPharmacol5:149–154.DENECHAUDPD,GIRARDJANDPOSTICC.2008a.Carbo-hydrateresponsiveelementbindingproteinandlipidhomeostasis.CurrOpinLipidol19:301–306.DENECHAUDPD,DENTINR,GIRARDJANDDPOSTICC.2008b.RoleofChREBPinhepaticsteatosisandinsulinresistance.FEBSLett582:68–73.DIEZJJANDIGLESIASP.2003.Theroleofthenoveladipo-cyte-derivedhormoneadiponectininhumandisease.EurJEndocrinol148:293–300.DOCARMOMG,DONASCIMENTOCM,MARTÍN-HIDAL-GOAMANDHERRERAE.1996.Effectsofethanolin-takeonlipidmetabolisminthelactatingrat.Alcohol13:443–448.DOLNIKOFFMS,KATERCE,EGAMIM,DEANDRADEISANDMARMOMR.1988.Neonataltreatmentwithmonosodiumglutamateincreasesplasmacorticosteroneintherat.Neuroendocrinology48:645–649.DOOLITTLEMH,BEN-ZEEVO,ELOVSONJ,MARTINDANDKIRCHGESSNERTG.1990.Theresponseoflipo-proteinlipasetofeedingandfasting.Evidenceforpost-translationalregulation.JBiolChem265:4570–4577.DORANAC,MELLERN,CUTCHINSA,DELIRIH,SLAY-TONRP,OLDHAMSN,KIMJB,KELLERSRANDMC-NAMARACA.2008.Thehelix-loop-helixfactorsId3andE47arenovelregulatorsofadiponectin.CircRes103:624–634.DULLOOAG,MENSIN,SEYDOUXJANDGIRARDIERL.1995.Differentialeffectsofhigh-fatdietsvaryinginfattyacidcompositionontheefciencyofleanandfattissuedepositionduringweightrecoveryafterlowfoodintake.Metabolism44:273–279.ENGSTROMG,STAVENOWL,HEDBLADB,LINDP,ERIKS-SONKF,JANZONLANDLINDGARDEF.2003.Inam-mation-sensitiveplasmaproteins,diabetes,andmortal-ityandincidenceofmyocardialinfarctionandstroke:apopulation-basedstudy.Diabetes52:442–447.ESTADELLAD,OYAMALM,DÂMASOAR,RIBEIROEBANDOLLERDONASCIMENTOCM.2004.Effectofpalatablehyperlipidicdietonlipidmetabolismofseden-taryandexercisedrats.nutrition20:218–224.FAGGIONIR,FANTUZZIG,FULLERJ,DINARELLOCA,FEINGOLDKRANDGRUNFELDC.1998.IL-1betame-diatesleptininductionduringinammation.AmJPhysiol274:R204–R208.FAINJN,BAHOUTHSWANDMADANAK.2004.TNF-releasebythenonfatcellsofhumanadiposetissue.IntJObesRelatMetabDisord28:616–622.FERNÁNDEZ-QUINTELAA,CHURRUCAIANDPORTILLOMP.2007.Theroleofdietaryfatinadiposetissuemetabolism.PublicHealthNutr10:1126–1131.FICKOVAM,HUBERTP,CRÉMELGANDLERAYC.1998.Dietary(n-3)and(n-6)polyunsaturatedfattyacidsrapidlymodifyfattyacidcompositionandinsulineffectsinratadipocytes.JNutr128:512–519.FLACHSP,MOHAMED-ALIV,HORAKOVAO,ROSSMEISLM,HOSSEINZADEH-ATTARMJ,HENSLERM,RUZI-CKOVAJANDKOPECKYJ.2006.Polyunsaturatedfattyacidsofmarineorigininduceadiponectininmicefedahigh-fatdiet.Diabetologia49:394–397.AnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:26—page463—#11 DIETARYFATANDWHITEADIPOSETISSUE463FRIEDSK,RUSSELLCD,GRAUSONLANDBROLINRE.1993.Lipoproteinlipaseregulationbyinsulinandgluco-corticoidinsubcutaneousandomentaladiposetissuesofobesewomenandmen.JClinInvest92:2191–2198.FRIEDRICHSWE,NAVARIJO-ASHBAUGHAL,BOWMANBHANDYANGF.1995.Expressionandinammatoryregulationofhaptoglobingeneinadipocytes.BiochemBiophysResCommun209:250–256.FRÜHBECKG,GÓMEZ-AMBROSIJ,MURUZABALFJANDBURRELLMA.2001.Theadipocyte:amodelforin-tegrationofendocrineandmetabolicsignalinginenergymetabolismregulation.AmJPhysiol280:E827–E847.GAÍVAMH,COUTORC,OYAMALM,COUTOGE,SIL-VEIRAVL,RIBERIOEBANDNASCIMENTOCM.2001.Polyunsaturatedfattyacid-richdiets:effectonadiposetis-suemetabolisminrats.BrJNutr86:371–377.GOODRIDGEAGANDBALLEG.1965.Studiesonthemeta-bolismofadiposetissue.18.Invitroeffectsofinsulin,epinephrineandglucagononlipolysisandglycolysisinpigeonadiposetissue.CompBiochemPhysiol16:367–381.GORINE,TAL-ORZANDSHAFRIRE.1969.Glyceroneoge-nesisinadiposetissueoffasted,diabeticandtriamcinolonetreatedrats.EurJBiochem8:370–375.HILLJO,PETERSJC,LIND,YAKUBUF,GREENEHANDSWIFTL.1993.Lipidaccumulationandbodyfatdistri-butionisinuencedbytypeofdietaryfatfedtorats.IntJObesRelatMetabDisord17:223–236.HIVERTMF,SULLIVANLM,FOXCS,NATHANDM,D'AGOSTINORBSR,WILSONPWANDMEIGSJB.2008.AssociationsofAdiponectin,Resistin,andTNF-withInsulinResistance.JClinEndocrinolMetabMay20.HOLLENBERGCH,RABENMSANDASTWOODEB.1961.Thelipolyticresponsetocorticotropin.Endocrinology68:589–598.HOTAMISLIGILGS,PERALDIP,BUDAVARIA,ELLISR,WHITEMFANDSPIEGELMANBM.1996.IRS-1-medi-atedinhibitionofinsulinreceptortyrosinekinaseactivityinTNF-andobesity-inducedinsulinresistance.Science271:665–668.HOTTAKETAL.2000.Plasmaconcentrationsofanovel,adipose-specicprotein,adiponectin,intype2diabeticpatients.ArteriosclerThrombVascBiol20:1595–1599.HUFB.2003.Overweightandobesityinwomen:healthrisksandconsequences.JWomen’sHealth(Larchmt)12:163–172.IBRAHIMA,NATRAJANSANDGHAFOORUNISSAR.2005.Dietarytrans-fattyacidsalteradipocyteplasmamem-branefattyacidcompositionandinsulinsensitivityinrats.MetabClinExp54:240–246.IRITANIN,FUKUDAHANDTADAK.1996.Nutritionalregulationoflipogenicenzymegeneexpressioninratepi-didimaladiposetissue.JBiochem120:242–248.JAWORSKIK,SARKADI-NAGYE,DUNCANRE,AHMA-DIANMANDSULHS.2007.Regulationoftriglyceridemetabolism.IV.Hormonalregulationoflipolysisinadi-posetissue.AmJPhysiolGastrointestLiverPhysiol293:G1–G4.JÉQUIERE.2002.Pathwaystoobesity.IntJObesRelatMetabDisordSuppl2:S12–S17.KIRCHGESSNERTG,UYSALKT,WIESBROCKSM,MARI-NOMWANDHOTAMISLIGILGS.1997.Tumornecrosisfactor-alphacontributestoobesity-relatedhyperleptine-miabyregulatingleptinreleasefromadipocytes.JClinInvest100:2777–2782.KRAEMERFB,TAKEDAD,NATUVANDSZTALRYDC.1998.Insulinregulateslipoproteinlipaseactivityinratadiposecellsviawortmannin-andrapamycin-sensitivepathways.Metabolism47:555–559.KRATCHMAROVALETAL.2002.Aproteomicapproachforidenticationofsecretedproteinsduringthedifferen-tiationof3T3-L1preadipocytestoadipocytes.MolCellProteom1:213–222.LANGHANSWANDHRUPKAB.1999.Interleukinsandtu-mornecrosisfactorasinhibitorsoffoodintake.Neuropep-tides33:415–424.LARGEV,PERONIO,LETEXIERD,RAYHANDBEYLOTM.2004.Metabolismoflipidsinhumanwhiteadipocyte.DiabetesMetab30:294–309.LEEJY,SOHNKH,RHEESHANDHWANGD.2001.Satu-ratedfattyacids,butnotunsaturatedfattyacids,inducetheexpressionofcyclooxygenase-2mediatedthroughToll-likereceptor4.JBiolChem276:16683–16689.LEONARDWR,ROBERTSONML,SNODGRASSJJANDKUZAWACW.2003.Metaboliccorrelatesofhominidbrainevolution.CompBiochemPhysiolAMolIntegrPhysiol136:5–15.LINS,THOMASTC,STORLIENLHANDHUANGXF.2000a.Developmentofhighfatdiet-inducedobesityandleptinresistanceinC57Bl/6Jmice.IntJObesRelatMetabDisord24:639–646.LINY,LEEH,BERGAH,LISANTIMP,SHAPIROLANDSCHERERPE.2000b.Thelipopolysaccharide-activatedtoll-likereceptor(TLR)-4inducessynthesisofthecloselyAnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:26—page464—#12 464CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMArelatedreceptorTLR-2inadipocytes.JBiolChem275:24255–24263.MALJETAL.2004.Preventionofobesityandinsulinresis-tanceinmicelackingplasminogenactivatorinhibitor1.Diabetes53:336–346.MACKIEWICZA,SPEROT,GANAPATHIMKANDKUSH-NERI.1991.Effectsofcytokinecombinationsonacutephaseproteinproductionintwohumanhepatomacelllines.JImmunol146:3032–3037.MAEDAK,OKUBOK,SHIMOMURAI,FUNAHASHIT,MATSUZAWAYANDMATSUBARAK.1996.cDNAcloningandexpressionofanoveladiposespeciccol-lagen-likefactor,apM1(AdiposeMostabundantGenetranscript1).BiochemBiophysResCommun221:286–289.MOHAMED-ALIV,PINKNEYJHANDCOPPACKSW.1998.Adiposetissueasanendocrineandparacrineorgan.IntJObesity22:1145–1158.MOUSTAÏDN,JONESBHANDTAYLORJW.1996.Insulinincreaseslipogenicenzymeactivityinhumanadipocytesinprimaryculture.JNutr126:865–870.NADERALIEK,ESTADELLAD,ROCHAM,PICKAVANCELC,FATANIS,DENISRGANDWILLIAMSG.2003.Afat-enriched,glucose-enricheddietmarkedlyattenuatesadiponectinmRNAlevelsinratepididymaladiposetis-sue.ClinSci(Lond)105:403–408.NASCIMENTOCO,HUNTERLANDTRAYHURNP.2004.Regulationofhaptoglobingeneexpressionin3T3-L1adi-pocytesbycytokines,catecholamines,andPPARgamma.BiochemBiophysResCommun313:702–708.NASCIMENTOCURICM,MARMOMR,EGAMIM,RIBEI-ROEB,ANDRADEISANDDOLNIKOFFMS.1991.Ef-fectofmonosodiumglutamatetreatmentduringneona-taldevelopmentonlipogenesisrateandlipoproteinlipaseactivityinadultrats.BiochemInt24:927–935.NESCHENS,MORINOK,ROSSBACHERJC,PONGRATZRL,CLINEGW,SONOS,GILLUMMANDSHULMANGI.2006.Fishoilregulatesadiponectinsecretionbyaperoxisomeproliferator-activatedreceptor-gamma-de-pendentmechanisminmice.Diabetes55:924–928.OLLERDONASCIMENTOCMANDWILLIAMSONDH.1986.Evidenceforconservationofdietarylipidintheratduringlactationandtheimmediateperiodafterremovalofthelitter.Decreasedoxidationoforal[1-14C]triolein.BiochemJ239:233–236.OLLERDONASCIMENTOCMANDWILLIAMSONDH.1988.Tissue-speciceffectsofstarvationandrefeedingonthedisposaloforal[1-14C]trioleinintheratduringlactationandonremovaloflitter.BiochemJ254:539–546.OLLERDONASCIMENTOCM,ILICVANDWILLIAMSONDH.1989.Re-examinationoftheputativerolesofin-sulinandprolactinintheregulationoflipiddepositionandlipogenesisinvivoinmammaryglandandwhiteandbrownadiposetissueoflactatingratsandlitter-removedrats.BiochemJ258:273–278.OLSWANGY,COHENH,PAPOO,CASSUTOH,CRONIGERCM,HAKIMIP,TILGHMANSM,HANSONRWANDRESHEFL.2002.Amutationintheperoxisomeprolifera-tor-activatedreceptorgamma-bindingsiteinthegeneforthecytosolicformofphosphoenolpyruvatecarboxykinasereducesadiposetissuesizeandfatcontentinmice.ProcNatlAcadSciUSA99:625–630.OTTODA,BALTZELLJKANDWOOTENJT.1992.Reduc-tionintriacylglycerollevelsbyshoilcorrelateswithfreefattyacidlevelsinadlibitumfedrats.Lipids.27:1013–1017.OYAMALM,BUENOAA,ESTADELLAD,MOTOYAMACSMANDNASCIMENTOCO.2005.regulationofhap-toglobingeneexpressionin3T3-L1adipocytesbyfattyacids.ObesityReview6:46.PAJOVICS,JONESVE,PROWSEKR,BERGERFGANDBAUMANNH.1994.Species-specicchangesinregula-toryelementsofmousehaptoglobingenes.JBiolChem269:2215–2224.PÉNICAUDL,COUSINB,LELOUPC,LORSIGNOLAANDCASTEILLAL.2000.Theautonomicnervoussystem,adiposetissueplasticity,andenergybalance.Nutrition16:903–908.PÉREZ-MATUTEP,PÉREZ-ECHARRIN,MARTÍNEZJA,MARTIAANDMORENO-ALIAGAMJ.2007.Eicos-apentaenoicacidactionsonadiposityandinsulinresis-tanceincontrolandhigh-fat-fedrats:roleofapoptosis,adiponectinandtumournecrosisfactor-alpha.BrJNutr97:389–398.PISANILP,OLLERDONASCIMENTOCM,BUENOAA,BIZC,ALBUQUERQUEKT,RIBEIROEBANDOYAMALM.2008a.HydrogenatedfatdietintakeduringpregnancyandlactationmodiesthePAI-1geneexpressioninwhiteadiposetissueofoffspringinadultlife.LipidsHealthDis7:13–22.PISANILP,OYAMALM,BUENOAA,BIZC,ALBUQUER-QUEKT,RIBEIROEBANDOLLERDONASCIMENTOCM.2008b.HydrogenatedfatintakeduringpregnancyandlactationmodiesserumlipidproleandadipokinemRNAin21-day-oldrats.Nutrition24:255–261.AnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:26—page465—#13 DIETARYFATANDWHITEADIPOSETISSUE465PONDCM.1999.Physiologicalspecialisationofadiposetis-sue.ProgLipidRes38:225–248.POPKINBM.1998.Thenutritiontransitionanditshealthimplicationsinlower-incomecountries.PublicHealthNutr1:5–21.PRINSJB.2002.Adiposetissueasanendocrineorgan.BestPractResClinEndocrinolMetab16:639–651.RACLOTT.2003.Selectivemobilizationoffattyacidsfromadiposetissuetriacylglycerols.ProgLipidRes42:257–288.RACLOTTANDGROSCOLASR.1994.Individualsh-oiln-3polyunsaturatedfattyaciddepositionandmobiliza-tionratesforadiposetissueofratsinanutritionalsteadystate.AmJClinNutr60:72–78.REAVENGM.1988.Bantinglecture1988.Roleofinsulinresistanceinhumandisease.Diabetes37:1595–1607.REGAGETAL.2005.Inammatorycytokinesinterleukin-6andoncostatinminduceplasminogenactivatorinhibitor-1inhumanadiposetissue.Circulation111:1938–1945.RESHEFL,OLSWANGY,CASSUTOH,BLUMB,CRONIGERCM,KALHANSC,TILGHMANSMANDHANSONRW.2003.Glyceroneogenesisandthetriglyceride/fattyacidcycle.JBiolChem278:30413–30416.RIBEIROEB,DONASCIMENTOCM,ANDRADEIS,HI-RATAAEANDDOLNIKOFFMS.1997.Hormonalandmetabolicadaptationstofastinginmonosodiumgluta-mate-obeserats.JCompPhysiol[B]167:430–437.ROBERTSCK,BARNARDRJ,LIANGKHANDVAZIRIND.2002.Effectofdietonadiposetissueandskeletalmus-cleVLDLreceptorandLPL:implicationsforobesityandhyperlipidemia.Atherosclerosis161:133–141.RODBELLMANDJONESAB.1966.Metabolismofisolatedfatcells.3.Thesimilarinhibitoryactionofphospholi-paseC(Clostridiumperfringensalphatoxin)andofin-sulinonlipolysisstimulatedbylipolytichormonesandtheophylline.JBiolChem241:140–142.ROTHWELLNJ,STOCKMJANDTRAYHURNP.1983.Re-ducedlipogenesisincafeteria-fedratsexhibitingdiet-in-ducedthermogenesis.BiosciRep3:217–224.RUSHEC,PLANKLDANDYAJNIKCS.2007.Interleukin-6,tumournecrosisfactor-alphaandinsulinrelationshipstobodycomposition,metabolismandrestingenergyex-penditureinamigrantAsianIndianpopulation.ClinEn-docrinol66:684–690.RUSTANAC,HUSTVEDTBEANDDREVONCA.1993.Di-etarysupplementationofverylong-chainn-3fattyacidsdecreaseswholebodylipidutilizationintherat.JLipidRes34:1299–1309.SACKSFMANDKATANM.2002.Randomizedclinicaltrialsontheeffectsofdietaryfatandcarbohydrateonplasmalipoproteinsandcardiovasculardisease.AmJMed113:13S–24S.SAKAMOTOK,SAKAMOTOTANDOGAWAH.2008.Effectsofmetabolicriskfactorsonproductionofplasminogenactivatorinhibitor-1andadiponectinbyadipocytes.CircJ72:844–846.SALMENNIEMIU,ZACHAROVAJ,RUOTSALAINENE,VAUHKONENI,PIHLAJAMÄKIJ,KAINULAINENS,PUNNONENKANDLAAKSOM.2005.Associationofadiponectinlevelandvariantsintheadiponectingenewithglucosemetabolism,energyexpenditure,andcyto-kinesinoffspringoftype2diabeticpatients.JClinEn-docrinolMetab90:4216–4223.SARTINJL,LAMPERTIAAANDKEMPPAINENRJ.1985.Alterationsininsulinandglucagonsecretionbymono-sodiumglutamatelesionsofthehypothalamicarcuatenu-cleus.EndocrRes11:145–155.SAWDEYMSANDLOSKUTOFFDJ.1991.Regulationofmurinetype1plasminogenactivatorinhibitorgeneexpres-sioninvivo:tissuespecicityandinductionbylipopoly-saccharide,tumornecrosisfactor-alpha,andtransforminggrowthfactor-beta.JClinInvest88:1346–1353.SCRIBAPC,BAUERM,EMMERTD,FATEH-MOGHADAMA,HOFMANNGG,HORNKANDPICKARDTCR.1979.Effectsofobesity,totalfastingandre-alimentationonL-thyroxine(T4),3,5,3'-L-triiodothyronine(T3),3,3',5'-L-triiodothyronine(rT3),thyroxinebindingglobulin(TBG),cortisol,thyrotrophin,cortisolbindingglobulin(CBG),transferrin,alpha2-haptoglobinandcomplementC'3inserum.ActaEndocrinol(Copenh)91:629–643.SEGARRAAETAL.2001.Circulatinglevelsofplasmino-genactivatorinhibitortype-1,tissueplasminogenactiva-tor,andthrombomodulininhemodialysispatients:bio-chemicalcorrelationsandroleasindependentpredictorsofcoronaryarterystenosis.JAmSocNephrol12:1255–1263.SENGENESC,STICHV,BERLANM,HEJNOVAJ,LAFON-TANM,PARISKOVAZANDGALITZKYJ.2002.In-creasedlipolysisinadiposetissueandlipidmobilizationtonatriureticpeptidesduringlow-caloriedietinobesewomen.IntJObesRelatMetabDisord26:24–32.SEOJBETAL.2004.Adipocytedetermination-anddif-ferentiation-dependentfactor1/sterolregulatoryelement-bindingprotein1cregulatesmouseadiponectinexpres-sion.JBiolChem279:22108–22117.SHIH,KOKOEVAMV,INOUYEK,TZAMELII,YINHANDFLIERJS.2006.TLR4linksinnateimmunityandfattyAnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:26—page466—#14 466CLÁUDIAM.OLLERDONASCIMENTO,ELIANEB.RIBEIROandLILAM.OYAMAacid-inducedinsulinresistance.JClinInvest116:3015–3025.SHILLABEERGANDLAUDC.1994.Regulationofnewfatcellformationinrats:theroleofdietaryfats.JLipidRes35:592–600.SHIMOMURAY,TAMURATANDSUZUKIM.1990.Lessbodyfataccumulationinratsfedasafoweroildietthaninratsfedabeeftallowdiet.JNutr120:1291–1296.SILVAAP,GUIMARÃESDE,MIZURINIDM,MAIAIC,ORTIZ-COSTAS,SARDINHAFLANDDOCARMOMG.2006.Dietaryfattyacidsearlyinlifeaffectlipidmeta-bolismandadiposityinyoungrats.Lipids41:535–541.SINGERP,WIRTHMANDBERGERI.1990.Apossiblecon-tributionofdecreaseinfattyacidstolowserumtriglyc-eridelevelsafterdietssupplementedwithn-6andn-3polyunsaturatedfattyacids.Atherosclerosis83:167–175.SLAVINBG,ONGJMANDKERNPA.1994.Hormonalreg-ulationofhormone-sensitivelipaseactivityandmRNAlevelsinisolatedratadipocytes.JLipidRes.35:1535–1541.STEINBERGGR,BONENAANDDYCKDJ.2002.Fattyacidoxidationandtriacylglycerolhydrolysisareenhancedafterchronicleptintreatmentinrats.AmJPhysiolEndo-crinolMetab282:E593–E600.STRÄLFORSPANDHONNORRC.1989.Insulin-inducedde-phosphorylationofhormone-sensitivelipase.CorrelationwithlipolysisandcAMP-dependentproteinkinaseactiv-ity.EurJBiochem182:379–385.TAKEUCHIH,MATSUOT,TOKUYAMAK,SHIMOMURAYANDSUZUKIM.1995.Dietinducedthermogenesisislowerinratsfedalarddietthaninthosefedahigholeicacidsafoweroildiet,asafoweroildietoralinseedoildiet.JNutr125:920–925.TODORICJ,LOFFLERM,HUBERJ,BILBANM,REIMERSM,KADLA,ZEYDAM,WALDHAUSLWANDSTUL-NIGTM.2006.Adiposetissueinammationinducedbyhigh-fatdietinobesediabeticmiceispreventedbyn-3polyunsaturatedfattyacids.Diabetologia49:2109–2119.TRAVERSMTANDBARBERMC.1999.Insulin-glucocorti-coidinteractionsintheregulationofacetyl-CoAcarbo-xylase-alphatranscriptdiversityinovineadiposetissue.JMolEndocrinol22:71–79.TRAYHURNPANDBEATTIEJH.2001.Physiologicalroleofadiposetissue:whiteadiposetissueasanendocrineandsecretoryorgan.ProcNutrSoc60:329–339.TSUBOYAMA-KASAOKAN,TAKAHASHIM,KIMHANDEZAKIO.1999.Up-regulationofliveruncouplingpro-tein-2mrnabyeithershoilfeedingorbrateadmin-istrationinmice.BiochemBiophysResCommun257:879–885.TSUKUMODMETAL.2007.Loss-of-functionmutationinToll-likereceptor4preventsdiet-inducedobesityandinsulinresistance.Diabetes56:1986–1998.UYSALKT,WIESBROCKSM,MARINOMWANDHOTA-MISLIGILGS.1997.Protectionfromobesity-inducedin-sulinresistanceinmicelackingTNF-function.Nature389:610–614.VAUGHANM,BERGERJEANDSTEINBERGD.1964.Hor-mone-sensitivelipaseandmonoglyceridelipaseactivitiesinadiposetissue.JBiolChem239:401–409.VENTREJ,DOEBBERT,WUM,MACNAULK,STEVENSK,PASPARAKISM,KOLLIASGANDMOLLERDE.1997.Targeteddisruptionofthetumornecrosisfactor-alphagene:metabolicconsequencesinobeseandnono-besemice.Diabetes46:1526–1531.VOLPEJJANDMARASAJC.1975.Hormonalregulationoffattyacidsynthetase,acetyl-CoAcarboxylaseandfattyacidsynthesisinmammalianadiposetissueandliver.Bio-chimBiophysActa380:454–472.WEISBERGS,MCCANND,DESAIM,ROSENBAUMM,LEIBELRLANDFERRANTEJRAW.2003.Obesityisassociatedwithmacrophageaccumulationinadiposetis-sue.JClinInvest112:1796–1808.YAMAMOTOY,HIROSEH,SAITOI,TOMITAM,TANI-YAMAM,MATSUBARAK,OKAZAKIY,ISHIIT,NISHI-KAIKANDSARUTAT.2002.Correlationoftheadipo-cyte-derivedproteinadiponectinwithinsulinresistanceindexandserumhigh-densitylipoprotein-cholesterol,in-dependentofbodymassindex,intheJapanesepopula-tion.ClinSci(Lond)103:137–142.ZAVARONII,NUMEROSOF,DONGIOVANNIP,ARDIGOD,VALENTIL,FRACANZANIA,VALTUENAS,DELSIG-NORER,FARGIONSANDREAVENGM.2003.Whatisthecontributionofdifferencesinthreemeasuresoftu-mornecrosisfactor-alphaactivitytoinsulinresistanceinhealthyvolunteers?Metabolism52:1593–1596.ZHOUX,DESCHEPPERJ,DECRAEMERD,DELHASEM,GYSG,SMITZJANDHOOGHE-PETERSEL.1998.Pituitarygrowthhormonereleaseandgeneexpressionincafeteria-diet-inducedobeserats.JEndocrinol159:165–172.AnAcadBrasCienc(2009)81(3)