Linoleic acid–good or bad for the brain? | npj Science of ...

Linoleic acid (LA, 18:2n-6) is an essential n-6 polyunsaturated fatty acid (PUFA) required for normal growth and development at 1 to 2% of ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature npjscienceoffood reviewarticles article Linoleicacid–goodorbadforthebrain? DownloadPDF DownloadPDF Subjects NeurochemistryOils APublisherCorrectiontothisarticlewaspublishedon01April2020 Thisarticlehasbeenupdated AbstractIncreasedintakeofomega-6richplantoilssuchassoybeanandcornoiloverthepastfewdecadeshasinadvertentlytripledtheamountofn-6linoleicacid(LA,18:2n-6)inthediet.AlthoughLAisnutritionally“essential”,verylittleisknownabouthowitaffectsthebrainwhenpresentinexcess.ThisreviewprovidesanoverviewonthemetabolismofLAbythebrainandtheeffectsofexcessdietaryLAintakeonbrainfunction.Pre-clinicalevidencesuggeststhatexcessdietaryLAincreasesthebrain’svulnerabilitytoinflammationandlikelyactsviaitsoxidizedmetabolites.Inhumans,excessmaternalLAintakehasbeenlinkedtoatypicalneurodevelopment,butunderlyingmechanismsareunknown.ItisconcludedthatexcessdietaryLAmayadverselyaffectthebrain.ThepotentialneuroprotectiveroleofreducingdietaryLAmeritsclinicalevaluationinfuturestudies. IntroductionLinoleicacid(LA,18:2n-6)isanessentialn-6polyunsaturatedfattyacid(PUFA)1requiredfornormalgrowthanddevelopmentat1to2%ofdailyenergy.2LAhasbecomeubiquitousinWesterndietsoverthepastfewdecadesduetoagriculturalshiftstowardshigh-LAsoybeanandcornoilsduringthelate1930s,resultinginagreaterthan3-foldincreaseinintake.3,4HistoriclevelsofLAintakerangedbetween1to2%ofdailycaloriespre-1930s,butcurrentlyaveragemorethan7%ofdailycalories.4Basedoneconomicdisappearancedata,themajorityofLAintheUSdietcomesfromsoybeanoil.4AmongstotherdietaryPUFAsimportantforoptimalhealth,LAistheonlyonethathasmarkedlychangedinthedietoverthepastfewdecades.Contrarytocommonmisconception,theintakeofLA’selongation-desaturationproduct,arachidonicacid(AA,20:4n-6),andtheessentialn-3fattyacid,alpha-linolenicacid(ALA,18:3n-3),anditselongation-desaturationproductseicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA),hasremainedrelativelyconstantat<1%energysincetheearly1900s.4ExcessLAinthefoodsupplyhasshiftedthen-6ton-3ratiofrom4:1to20:1.4,5Surprisingly,littleisknownabouthowthisincreaseindietaryLAaffectsthebrain.ItismainlyviewedasanessentialprecursortoAA,whichisimportantforneurodevelopmentandotherphysiologicalprocesses.6Despitebeingamajorpartofthediet,LAhasbeenconsiderednon-functionalinthebrainbecauseofitslowconcentration(<2%oftotalfattyacids)comparedtopalmiticacid(16:0),stearicacid(18:0),oleicacid(18:1n-9),DHA,andAAwhichmakeupover84%ofbrainfattyacidsinratsandhumans.7,8LAisknowntoenterthebrainatarateof~4 pmol/g/s,whichiscomparabletotherateofentryofAA,DHA,andotherfattyacidsintothebrain.9,10However,unlikeAAandDHAwhichmostlyincorporateintobrainmembranephospholipids,themajority(~59%)ofLAenteringthebrainisrapidlyβ-oxidizedintoaqueousproducts,likelycomposedofcarbondioxide,acetate,andotherpolarmetabolitesofβ-oxidation.9Someofthe2-carbonacetatemoleculesproducedbyβ-oxidationarerecycledintocholesterolviadenovolipidsynthesispathwayswithinthebrain.9,11LAisalsoaprecursortooxidizedproductsknownas‘oxidizedlinoleicacidmetabolites’(OXLAMs)thatareproducedbyauto-oxidationorenzymaticallyvialipoxygenase(LOX),cyclooxygenase(COX),cytochromeP450(CYP450),andsolubleepoxidehydrolase(sEH).12,13,14,15OXLAMsarelipidmediatorsknowntoregulatepainandinflammatorysignalinginperipheraltissue,16,17,18,19wheretheyareabundant.18,20Inthebrain,theyarepresumedtobeformedbyLOX,COX,CYP450,andsEHenzymes,buttheirrolethereisnotfullyunderstood.ThisreviewhighlightsthecurrentstateofknowledgeontheroleandmetabolismofLAandOXLAMsinthebrain.StudieslinkingLAandOXLAMstoreportedbiochemical,neuropathological,orbehavioralendpointsinchickens,rodents,andhumansarediscussed,anddirectionsforfutureresearchareproposed.EffectsofLAorOXLAMsonchickensStudiesinthelate1950sand1970sshowedthatchicksfedavitamin(V)-EdeficientdietcontainingLAdevelopedencephalomalacia,21,22,23,24,25aneurodegenerativeconditioncharacterizedbynecrosis,edema,andmicrovasculatureabnormalitiesthatcanleadtoataxiaanddeath.26Table1providesadetailedsummaryofallthesestudies,whicharediscussedherein.Table1EffectofLAorOXLAMsonneurologicaloutcomesinchickens.FullsizetableDametal.reportedthat2-day-oldchicksfedaV-Edeficientdietcontaining1.5%ethyl-LA(weightpercent)fromthe2nddayoflifeonwards,diedfromencephalomalaciawithin28days(11outof12chicks),comparedtochicksfedaV-Edeficientdietcontainingethyl-ALA(0outof12)oraV-EdeficientbasaldietlackingbothLAandALA(0outof12).21Inafollow-upstudy,theauthorsfoundthataV-Edeficientdietcontaining1.5%ethyl-AAinducedencephalomalaciafasterthanaV-Edeficientdietcontaining1.5%ethyl-LAorlard(mixedsourceofLAandAA).24ThesestudiesdemonstratedthatwhenV-Eisabsentfromthediet,AAandtoalesserextentLA,damagethebrainofyoungchicks.ALAcausednodamage.Follow-upstudiesinchickensdemonstratedthatoxidizedLAmetabolites(i.e.,OXLAMs)werethelikelycauseofencephalomalacia,andthatthiseffectwaslinkedbymaternaldietaryLAcontent.BartovandBornsteinreportedthatmaternalintakeofa4%soybeanoil(relativelyhighinLA)or4%tallow(lowinLA)dietcontaining5or25 mg/kgα-tocopherolacetateeach,from6to11monthsofage,reducedegg-yolkLAconcentrationinthetallowgroup(independentofV-Edietarycontent),anddecreasedV-Econcentrationinyolkofbothgroupsfedthetallowandsoybeandietscontaininglowα-tocopherolacetate(5 mg/kg).23ChicksfromeachmaternalgroupwerethenfedaV-Efreedietcontaining4%or10%oxidizedsaffloweroilhighinLA(~70%)for31daystoinduceencephalomalacia.Oxidationwasachievedbyheatingtheoilat145 °Cfor24 h.Theauthorsreportedthatregardlessofsaffloweroilcontentofthechickdiet(4or10%level),chicksborntohensthatwerefedthe4%soybeanoildietcontaininglow(5 mg/kg)α-tocopherolacetatelevelsexperiencedasignificantlyhigherfrequencyofataxiaandmortalitycomparedtochicksbornhensfed4%soybeanoilcontaining25 mg/kgα-tocopherol,orbeeftallowcontainingeither5or25 mg/kgα-tocopherol.23Hence,ahighLAmaternaldietlowinV-Eacceleratedthedevelopmentofataxiaandencephalomalacia-relatedmortalityinchickoffspringmaintainedonaV-Efreedietcontainingoxidizedsaffloweroil.LoweringmaternaldietaryLAorsupplementingitwithV-Ewasprotective.Budowskietal.performedaseriesofexperimentstounderstandthecauseofataxiaandmortailitylinkedtoencephalomalacia.25TheyfedaV-Efreedietcontainingoxidizedsaffloweroilornon-heatedsaffloweroilmethylestersat4%or10%(w/w)tochicksfor2to3weeks.At4%oilcontent,theincidenceofataxiaandmortalitywerehigherinthegroupfedthenon-heatedsaffloweroilcomparedtothegroupfedoxidizedsaffloweroil.At10%,ataxiaandmortalitywerehigherinthegroupfedoxidizedsafflowercomparedtothegroupfednon-heatedsaffloweroil.ThefindingssuggestthatintheabsenceofV-E,oxidizedsaffloweroilat10%(w/w)inducedmoreneurologicaldeficitsthanat4%.Also,thefactthatataxiaanddeathwereobservedinthegroupfed4%non-heatedsaffloweroil,suggeststheabsenceofdietaryV-Emightinduceoilauto-oxidationofLA(themainPUFAinsaffloweroil).ItisnotknownwhethertheOXLAMspeciesgeneratedbyauto-oxidationduetotheabsenceofV-Einthediet,differfromthosegeneratedbyheating.Notably,thisstudydidnotincludeacontrolgroupprovidedwithV-Einthediet.TotestwhetherV-Ewasprotective,theauthorsprovided1-day-oldmalechickswithnon-heatedorheated10%(w/w)saffloweroilmethylesterslackingorcontaining1 µg/kgV-Efor19days.25Ataxiaandmortalitywererelativelyhighinthegroupsfednon-heatedoilslackingorcontainingV-E(65–70%ataxia;20–30%mortality).InthegroupsprovidedwithoxidizedoilwithorwithoutV-E,theincidenceofataxiaandmortalityweremuchincreased(90–95%ataxia,70%mortality),irrespectiveofV-Econtent.ItispossiblethathigherdosesofV-Emighthavebeenmoreeffectiveinreducingmortalityandtheincidenceofataxiabylimitingauto-oxidation,particularlyinthenon-heatedsaffloweroilgroup.Theauthorsalsointroducedthepolarfraction(at0.3%w/w)totheV-Efreedietcontaining4%saffloweroil,andfoundthatitinducedataxiaandincreasedmortalitycomparedtothesamebackgrounddietlackingthepolarextracts.25BecauseoleicacidandLAarethemainunsaturatedfattyacidsinsaffloweroil,theauthorsintroducedoleicacidandLAderivedketoneesters(i.e.,oxidizedfattyacids)at0.2%and0.12%,respectively,tothesameV-Efreedietscontaining4%saffloweroil.Theyfoundthattheincidenceofataxiawas50%and80%withtheoleicacidandLAketo-esters,respectively,andthushigherthanthedietslackingtheseoxidizedcompounds.AseparatestudybyKokatnuretal.showedthattheadditionof0.25%(w/w)12-oxo-cos-9-octadecenoicacid,12-oxo-octadecanoicacid,12-oxo-trans-10-octadecenoicacid,or12-oxo-cos-9-octadecenoicacidmethylestertoaV-Edeficientbasaldietcontaining10%cornoil,inducedencephalomalaciain42–100%ofchickenscomparedto17%inthosefedthebasaldiet.27Theauthorsalsodeterminedthataslittleas0.05%ofketonefattyacidsinducedencephalomalaciaandthatthiseffectwasexacerbatedbyaddingmorecornoiltothediet(from2.5to10%w/w).27ThesestudiesprovidedirectevidencethatOXLAMs,andtoalesserextentoxidizedoleicacidmetabolites,induceataxiaandmortalityduetoencephalomalaciainchickens.IntheBudowskietal.study,theadministrationoftheanti-coagulantdicumaroltoaV-Efreedietcontaining4%saffloweroilreducedtheincidenceofataxiaandmortality,25suggestingthattheneurotoxiceffectsofOXLAMsmaybecausedbybloodcoagulationanddisturbancesinthebrain’smicrovasculature.ThisisinagreementwithastudybyFischeretal.whoshowedmorphologicchangesincerebralvasculature,characteristicofpre-ceroidformationinadultchickensfedan8%LAdietlackingV-E,comparedtochickensonasimilardietcontainingV-E.22Fullydevelopedceroidshavebeenlinkedtoneurodegeneration.28EffectsofLAorOXLAMsonrodentsThefewstudiesthatexploredthedirectroleofLAanditsmetabolitesinrodentshaveshownthatLAisinvolvedinregulatingbrainimmunity,seizurethreshold,andneuronalsignaling,andthatsomeoftheseeffectsaremediatedbyitsoxidizedmetabolites(i.e.,OXLAMs).Inrats,LAloweringwasfoundtoattenuateLPS-inducedneuroinflammation,reducebrainconcentrationofpro-inflammatorylipidautacoidsandincreasebrainlevelsofanti-inflammatorylipidmediators.Tahaetal.reportedthatcomparedtoa“high”5.2%energyLAdiet,chronicconsumptionofa“low”0.4%energyLAdietfor15–18weeks,reducedtheincorporationrateofradiolabeledAAintothebrainandpreventedtheincreaseinbrainAA-derivedprostaglandinE2concentrationandCOX-2activityinducedby2-daylipopolysaccharide(LPS)administrationintothe4thventricle.29TwoindependentstudiesreportedthatdietaryLAlowering(from5.2%to0.4%energy)reducedbrainconcentrationsofpro-inflammatoryAA-derivedeicosanoids(e.g.,5-Hydroxyeicosatetraenoicacid)andincreasedconcentrationsofanti-inflammatoryEPAorDHAderivedmetabolites.30,31ThismaypartiallyexplainwhyLAloweringincreasedresiliencetoLPS-inducedneuroinflammationintheTahaetal.study.29AcuteadministrationofLAwasreportedtoconferseizureprotectioninrats.Wheninfusedintravenouslyatadoseof0.028 mg/kg,itdecreasedtheincidenceoftonic-clonicconvulsionsby3-fold,butincreasedtheincidenceofcorticalspike-wavedischargesby1.5to2folds.32Voskuyletal.showedthatintravenousadministrationof56–64 mg/kgLAraisedcorticalfocalandgeneralizedseizurethresholdsby3-foldand1.3–9.0-fold,respectively,inacorticalstimulationseizuremodelcomparedtosalineandoleicacidcontrols.33TheeffectofchronicLAadministrationonseizurethresholdshasnotbeentested.RecentstudiessuggestthattheeffectsofLAinthebrainarelikelymediatedbyOXLAMs.Hennebelleetal.showedthatOXLAMsareincreasedinvariousratbrainregionsfollowingacuteischemicinjury,possiblyduetotheirinvolvementintheresponsetoischemicbraininjury.34DirectapplicationofLAitselftorathippocampalslicesdidnotalterpaired-pulsefacilitationwithinsomaordendrites,whereasLA-derived13-hydroxyoxtadecadieonicacid(13-HODE)increasedsomaticpairedpulsefacilitation.34AlthoughtheHennebelleetal.studyraisesthepossibilitythatLA’seffectsonthebrainmightbemediatedbyOXLAMs,34itonlytestedoneOXLAM(13-HODE).Futurestudiesshouldaddresstheisolatedandcollectiveeffectsofotherhydrox,epoxy,dihydroxy,trihydroxy,andketonemetabolitesofLAonneurotransmissionandotherbrainprocesses.AlthoughOXLAMsareknowntobeabundantinrodentbrain,31,34itisnotknownwhethertheyarepreferentiallyformedinthebrainfromLA,orincorporateddirectlyfromcirculatingOXLAMsprovidedinthediet.Thisissuewasrecentlyaddressedbytwostudies.Tahaetal.fedratsagradedLAdiet(0.4%,5.2%,and10.4%energy)for15–18weeks,andshowedthatincreasingdietaryLAincreasedcerebralcortexandcerebellumOXLAMconcentrationsinadose-dependentmanner(Fig.1).31Inafollowupstudy,Ramsdenetal.fedmiceahighLAdiet(17%energy),oralowLAdiet(4%energy)withorwithoutoxidizedcornoilasasourceofOXLAMs.35TheauthorsfoundnoevidenceofdietaryOXLAMincorporationintothebrain,butconsistentwithapreviousreport,thehighLAdietincreasedbrainOXLAMconcentrationscomparedtothelowLAdietwithorwithoutOXLAMs.35ThesestudiessuggestthatdietaryOXLAMsarenotreadilyincorporatedintorodent(mouse)brain,andthatLAisthemainsourceofOXLAMsinthebrain.BehavioralstudiesondietaryOXLAMsinrodentsareyettobeperformed,ashasbeendonepreviouslyinchickens.Notably,althoughthechickenstudiesoutlinedinTable1showedaneffectofOXLAMsonbehavior,noneassessedtheirbioavailability.Inrodents,dietaryLAhydroperoxideswerereportedtodegradeintoaldehydesinthestomach,raisingthepossibilitythatthereportedeffectsofOXLAMsonthebrainmightbemediatedbytheirdegradationproducts.36Fig.1Effectofincreasingdietarylinoleicacid(LA)onunesterifiedoxidizedlinoleicacidmetabolite(OXLAM)concentrationsinratcerebralcortex.AdaptedfromTahaetal.,31EpOMEepoxyoctadecamonoenoicacid,THFtetrahydrofuran-diols,EKODEepoxyketooctadecenoicacid,HODEhydroxyoctadecadienoicacid,oxo-ODEOxo-octadecadienoicacid,DiHOMEdihydroxyoctadecamonoenoicacid,TriHOMEtrihydroxyoctadecamonoenoicacid.Dataaregraphedasmedianandinterquartileinterval(IQR)representingthe25thand75thpercentiles.*p 9.7%offattyacids)wasassociatedwithreducedmotorandcognitivescoresin2-to3-year-oldinfants.43Inthesamecohort,maternalbreastmilkLApercentcompositionwasassociatedwithreducedverbalIQat5to6yearsofage.44Infact,childrenbreastfedwiththehighestlevelsofLAhadcognitivescorescomparabletochildrenwhowereneverbreastfed.43TheseeffectswereindependentofAAorDHAbreastmilkcomposition,suggestingadirectimpactofexcessbreastmilkLA(andhencematernalintake)onbraindevelopment.Consistentwiththesefindings,LassekandGaulinfoundaninversecorrelationbetweenbreastmilkLApercentcompositionandcognitivescoresin15-year-oldchildren,suggestingalong-lastingimpactofmaternalLAonoffspringcognitiveskills.45Steenweg-deGraaffetal.alsoreportedasignificantpositiveassociationbetweenmaternalplasmaLAcompositionmeasuredatmid-pregnancyandtheriskofautistictraitsinchildrenattheageof6years.46AmorerecentstudyfoundthatprenatalintakeofdietshighintheratioofLAtoALA,wasassociatedwitha2-foldincreaseintheriskofdelayedpsychomotorandmentaldevelopmentalin6monthsinfants.47ConclusionPre-clinicalandclinicalstudiesdispelpreviousassumptionsthatLAisabenignfattyacidinthebrain.Onthecontrary,whenpresentinexcessandchronically,itinducesataxiainchickens,promotesneuroinflammationinratsandislinkedtoabnormalneurodevelopmentinhumans.LAadministeredacutelytoratsconfersseizureprotection,althoughitschroniceffectsonseizureshasnotbeentested.RecentanimalstudiessuggestthattheeffectsofLAmightbemediatedbyOXLAMsgeneratedfromLAenteringthebrain.AlthoughOXLAMsarepresentinthediet,48theextentoftheirbioavailabilityandaccumulationinthebrainfromdietarysourcesappearstobeminimal.35,36However,furtherassessmentoftheirdegradationproductsonbrainneurophysiologyandotherorgansiswarranted.ChronicconsumptionoflowLAdietsmightprotectthebrainagainstinflammation,asevidencedbyratstudiesshowingananti-inflammatorylipidomeinthebrainsofratsfedalowLAdiet,29,30,31andhumanstudiesshowingthatLAloweringcombinedwithEPAandDHAreducedheadachefrequencyinpatientswithdrug-resistantmigraines.38,39Inconclusion,thisreviewpresentsevidencethatexcessLAinthefoodsupplymightadverselyaffectthebrain.ThepotentialbenefitofLAloweringmeritsdetailedevaluationinwell-designedandadequately-poweredclinicalstudies,totestwhetherthistranslatesintotangiblereductionsintheriskofneurodegenerativedisordersandneurodevelopmentalabnormalitiesatapopulationlevel. 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DownloadreferencesAcknowledgementsTheauthoracknowledgesDr.ChrisRamsdenfordrawinghisattentiontosomeofthechickenstudiescitedherein.Dr.MarieHennebelleisthankedforcreatingFig.1.AuthorinformationAffiliationsDepartmentofFoodScienceandTechnology,CollegeofAgricultureandEnvironmentalSciences,UniversityofCalifornia,Davis,CA,95616,USAAmeerY.TahaAuthorsAmeerY.TahaViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsTheauthorwrotethepaper.CorrespondingauthorCorrespondenceto AmeerY.Taha.Ethicsdeclarations Competinginterests Theauthordeclaresnocompetinginterests. 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ReprintsandPermissionsAboutthisarticleCitethisarticleTaha,A.Y.Linoleicacid–goodorbadforthebrain?. npjSciFood4,1(2020).https://doi.org/10.1038/s41538-019-0061-9DownloadcitationReceived:03September2018Accepted:29October2019Published:02January2020DOI:https://doi.org/10.1038/s41538-019-0061-9SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Furtherreading ChemicalprofilingandantioxidantactivityofEquisetumramosissimumDesf.stemextract,apotentialtraditionalmedicinalplantforurinarytractinfections JeyalatchaganSureshkumar SingamoorthyAmalraj MuniappanAyyanar FutureJournalofPharmaceuticalSciences(2021) Artisanaloilobtainedfrominsects’larvae(Speciomerusruficornis):fattyacidscomposition,physicochemical,nutritionalandantioxidantpropertiesforapplicationinfood OrquídeaVasconcelosdosSantos PamelaCristinaSodréDias BarbaraElisabethTeixeira-Costa EuropeanFoodResearchandTechnology(2021) #Healthy:smartdigitalfoodsafetyandnutritioncommunicationstrategies—acriticalcommentary JulieL.Schiro LiranChristineShan PatrickWall npjScienceofFood(2020) DownloadPDF AssociatedContent Collection LeadingResearchinNeuroscience Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Collections FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation Contenttypes AbouttheEditors Contact OpenAccess ArticleProcessingCharges Editorialpolicies JournalMetrics AboutthePartner CallsforPapers Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies Closebanner Close SignupfortheNatureBriefingnewsletter—whatmattersinscience,freetoyourinboxdaily. 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