Biological Functions and Metabolism of Oleoylethanolamide

Biological functions and metabolism of oleoylethanolamide Clémentine Thabuis, Delphine Tissot-Favre, Jean-Baptiste Bezelgues, Jean-Charles Martin, Cristina Cruz-Hernandez, Fabiola Dionisi, Frédéric Destaillats

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Clémentine Thabuis, Delphine Tissot-Favre, Jean-Baptiste Bezelgues, Jean-Charles Martin, Cristina Cruz-Hernandez, et al.. Biological functions and metabolism of oleoylethanolamide. Lipids, Springer Verlag, 2008, 43 (10), pp.887-894. 10.1007/s11745-008-3217-y. hal-02658710

HAL Id: hal-02658710 https://hal.inrae.fr/hal-02658710 Submitted on 30 May 2020

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Copyright Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 19 18 17 16 15 14 13 12 11 10 25 24 22 21 20 5 9 8 4 1 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, 7 6 E-mail: [email protected] CH -1000LAUSANNE26,Switzerland Vers-chez-les-Blanc, P.O.Box44 Nestlé ResearchCenter Correspondence shouldbeaddressed: Clémentine Thabuis 3 2 published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans Running title: Fax: +41217858553 23 Tel.:+41 217858937 2 1 Nestlé ResearchCenter(Vers-chez-le INRA,UMR1260«Nutriments Lipidiqueset Biological FunctionsandMetabolismofOleoylethanolamide France ;UnivAix-Marseille1,2,FacultédeMédecine, Cristina Cruz-Hernandez Marseille, F-13385France;INSERM,U476, ROLESANDMETABOLISM OFOLEOYLETHANOLAMIDE 1-8. DOI: 10.1007/s11745-008-3217-y 1 , DelphineTissot-Favre Comment citer cedocument: IPHM-IFR 125,Marseille,F-13385France;

2 , FabiolaDionisi (Switzerland) s-Blanc, P.O.Box44,CH–1000LAUSANNE26,

2 , Jean-BaptisteBezelgues

/Finalversionofthemanuscript 10.1007/s11745-008-3217-y Prévention desMaladiesMétaboliques», 2 andFrédéricDestaillats 2 , Jean-CharlesMartin 2,*

1 1

Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 44 43 42 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, metabolism, lipidmetabolism. Key words: remains activewhenadministered orally. 41 the vagalnervethroughcapsaicinreceptors investigation ofthemechanism ofactionrevealedthatOEAactivatesPPAR-α food intakecontrol,lipid of TRVP1.Ithasbeendemonstrated thatOEA modulate lipidandglucosemetabolism andrecen control throughinteractionwithPPAR- derivatives havebeenneglecteduntilitwasde cannabinoid receptorsubtype1(CB1).Therolesofother ethanolamides hasbeenfocusseduntilrecently potential vanilloidtype1(TRPV1)receptorare through peroxisome proliferator-activatedreceptoralpha(PPAR- metabolism. Thebiological mechanism ofac oleoyethanolamide (OEA)withemphasis onits The presentreviewisfocussedonthe ABSTRACT published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans N-acylfattyacidethanolamine, foodintake,oleoylethanolamide, energy 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument: β

-oxidation, bodyweightlossandanalgesiceffects.The

α . Furtherinvestigationsdemonstrate thatOEA /Finalversionofthemanuscript monstrate thatOEAcanmodulate foodintake TRPV1. Pre-clinicalstudiesshowedthatOEA tion includingnon-genomic effectmediated have beneficialeffectsonhealthbyinducing metabolism andtheemerging roles of discussed. Theresearchrelatedtofattyacid t studyconfirmed thatOEAisanantagonist 10.1007/s11745-008-3217-y effectsonfoodintakecontrolandlipid onanandamide anditsinteractionwith N -acyl ethanolamine fattyacid α ) andtransientreceptor andstimulates 2 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 69 68 67 66 65 64 63 62 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 61 60 59 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, food restriction. Thelevelofthis endocannabi signals (2,4,5).Inbrain, theanandamide c intake may stimulate of theincreasedlevelOEA concentrations infoodproductsarereallylow(under 2 of plasmatic OEAafterfeedingcouldbedueto decreases duringfooddeprivationandincrease functions ofOEA,itsmetabolism andanalysis. (brush border).Thepresentreviewisfocussedontheserecentlydiscoveredbiological food intakevia powder (upto2µg/g),oatmeal ornuts(2,3). Biologically, theOEAfunctionistoregulate This molecule isnaturallypresentatlowc anorexigenic orbodyfatlossproperties,haveb formed from oleicacidandphosphatidylethanolamin increases foodintake.Anotherinterestingfa endogenous ligandforcannabinoidreceptorsubt has beenofgreatinterest.Inthelastdecad inflammatory properties(1).Among thisfamily, anandamide (derivedfrom arachidonic acid) Indeed, palmitoylethanolamide (derivedfrom plant andanimal tissues.Thesefattyacidderivativesappearedtohavebiologicalproperties. INTRODUCTION 1.1. Effectofoleoylethanolamide(OEA)onfoodintakecontrol 1. BIOLOGICALFUNCTIONSOFOLEOYLETHANOLAMIDE(OEA) published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans Fatty acidethanolamides (FAEA)belongto OEA issynthesizedinthesmall intestineof asynthesis/degradationbalance,whichoccursmainly intheenterocytes 1-8. DOI: 10.1007/s11745-008-3217-y N Comment citer cedocument: -acyltransferase activity andbiosynthesizedOEAcantriggersatiety is linkedtoanactivatedendogenoussynthesis. Indeedfood

oncentration significantly increasesuponsevere oncentrations infoodproductssuchascocoa tty acidamide isoleoylethanolamide (OEA), palmitic acid) haveanti-nociceptiveandanti- /Finalversionofthemanuscript e, itwasdiscoveredthatanandamide isan thepresenceofOEAinfood(2,3),but een extensivelystudiedoverthepastdecade. upon refeeding(2,4,5).Theincreasedlevel noid ismodulated inthe brainstructures 10.1007/s11745-008-3217-y ype 1(CB1).ActivatingCB1,anandamide variousvertebratespecies,whereitslevel a family oflipidsnaturallyfoundinboth e. BiologicalfunctionsofOEA,suchas μ g/g offood),suggestingthatonepart 3 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 94 93 92 91 90 89 88 87 86 85 84 83 82 81 80 79 78 77 76 75 74 73 72 71 70 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, all overtheexperiment (10). with adailyinjectionof 5mg OEA/kg bw,i control among theseexperimental periods.Neve over 14daysofexperiment butthedailyfoodin a globaldiminution offoodconsumption. Cumulative foodintakewassignificantly decreased until 14days.Indeed,subchronicintraperitoneal administration of5mg OEA/kg bwinduced were performed on24h-experiment. Theeffect 10 and5mg ofOEA/kgbwonthe24hoursfollo vehicles), thepercentagesoffoodintake dose-dependant decreaseoffoodintake.Compared been testedwithipadministration from 5to induced anyeffectsunderlyingtheperipheralac weight gaincompared tocontrol(7).Intracer and alloverthe9daysofexperiment inrats observed during4hoursafterintraperitoneal(ip)injectionofOEAat5mg/kg ofbodyweight fatty acidderivativecancontrolfoodintake central toinducefoodintakeandperipheralsatiety(5). respect tothenutritionalstatus,leadingapr to adecreaseoffoodintake.Similarly toananda leading toanincreaseoffoodintake,whereasintestinalOEAinducesasatietysignal anandamide activatescannabinoidreceptorsCB1mainly inthe mesolimbic system (6), (6). Anandamide andOEAwereshowntobe Anandamide levelsdonotchangeinthehypot according tothefeedingstatus,anddepe published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans Pharmacological studieshavebeenperformed tobetter understand howaverysimple 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument:

decrease were32,24and14%respectivelyfor20, nduced a3%significant decreaseofbodyweight 20mg/kg ofbodyweight,alwaysleadingtoa (7).Thesame treatment loweredalsothebody nding onspecificlocalizationinthebrain. ebroventricular administration ofOEAdidnot /Finalversionofthemanuscript . Asignificantdecreaseoffoodintakewas activethroughtwodistinctpathways.Thus, halamus butincreaseinthelimbic forebrain s ofOEAonfoodintakewerereproducible take wasnotsignificantlylowercompared to rtheless, thesubchronicOEAadministration, ecise controloffoodintake.Thisis mide, thenaturallevelsofOEAchangewith tion ofOEA(4).Variousdoseshave 10.1007/s11745-008-3217-y wing theinjection(8,9).Thesemeasures tothecontrol(animals injectedwith 4 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 120 119 118 117 116 115 114 113 112 111 110 109 108 107 106 105 104 103 102 101 100 99 98 97 96 95 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, strongly tofoodconsumption regulation. increased understarvation. Thealternativereleas PYY arereleasedduring thepost-prandialpe separately dependingonthenutritionalstatus stimulates appetite.Thesemolecules actalongth Cholecystokinin (CCK),andPeptideYY(PYY) that on thesynthesisofsatietysignalingbiomarkers showing thatOEAisprogressivelycatabolized(11). The ratioofintactOEAtohydrolyzeddecreasedalongthegastrointestinaltract, intestinal tissue.However,only0.48%ofth gastrointestinal tract(11).Thistreatment increasedtheOEAleveltoabout11times in rats bygavage(10mg/kg ofbodyweight),has administrated orally(11).Abioavailabilityst the degradationproductsofOEA,didnothaveanyinfluenceonfoodintakewhen increase ofthepostmeal intervals(12).Itha that OEAinducedadelayofthefirstmeal, a the small intestine (12).Severalmeal parameters together, theseresultssuggestthatOEAreducesfoodintakebyactingatalocalsitewithin corresponds tothetime forthecapsulestogofr OEA capsulesweresignificantlydifferentfrom effect wasobservedatafourfoldlowerleve When OEAwas administrated inpH-protectivecapsules(releasingOEAatpH6),asimilar significant decreaseoffoodintakeon24hwas acts peripherally(11).When OEAwasadministra published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans In parallel,studieshavebeenperformed Further studieslookingattheoraladminist 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument:

Ip injectionofOEAwasshown toreducetheghrelin e givendosewasfoundunchangedinthetissue. l (50mg/kg ofbodyweight)(12).Theeffects s beenshownthatethanolamine andoleicacid, udy, usingradiolabeledOEAadministrated to . ThesatietogenicpeptidesGLP-1,CCKand /Finalversionofthemanuscript been performed toassessOEAdegradationin decrease ofthesizefirstmeal andan controls5hoursafteradministration, what suchasGlucagonLikePeptide-1(GLP-1), to establishwhetherOEAhasanyinfluence havealsobeenmonitored anddemonstrated riod, whereastheghrelin plasma level is 10.1007/s11745-008-3217-y observed at200mg/kg oforalOEA(11). e ofthesedifferentbiomarkers contributes om thestomach tothesmall intestine.All ted bygavageatdifferentconcentrations,a ration effectofOEAconfirmed thatOEA e gastrointestinaltractandaresecreted havesatietogeniceffectsandghrelinthat 5 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 146 145 144 143 142 141 140 139 138 137 136 135 134 133 132 131 130 129 128 127 126 125 124 123 122 121 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, enterocytes isduetothe decreasedfoodintakeandbodyweightgain. OEA wouldenhance after OEAtreatment (7).Theseobservations s enterocytes, anincrease of FAT/CD36expressionandfattyaciduptake wasdemonstrated activated, thisreceptorinhibitsdifferenciati also anagonistofthecapsaicinreceptorTRPV FAT/CD36 expressionandofthefattyacidrelease cell culturesofenterocytesandadipocytes.In acid translocase)inadiposetissues(4).Follo Ip not onlyduetothedecreaseoffoodintakebutal than theoneobservedinpair-fedgroup,de de Fonseca 1.2. Effectsofoleoylethanolamide(OEA)onlipidmetabolism humans for therapeuticmetabolic health. properties thatwereobservedinin-vitro hormonal control ofsatiety.Neverthelessmore role intheperipheralcontrolof absorption andso,onfoodintakecontrol.Allt intestinal motility (15).Thedelayofthese gastrointestinal tractitself. Indeed,OEAdela satiety signals(8,13). unaffected (8).TheanorecticeffectsofOEAdo level, butnottheGLP-1concentrationin published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans administration of5mg/kg ofOEAinrats The modulation oflipidmetabolism byOEAwasinitiallydemonstrated byRodriguez Satietogenic propertiesofOEAcanalsobepartiallyexplainedbyitsactiononthe et al . (4).Indeed,OEAtreatment induced 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument: foodintakethathastobeintegratedwiththenervousand

studiesorinanimal models, areapplicableto ys gastricemptying (14),retardsandslowsdown wing thisobservation,OEA on ofpreadipocytesandadipogenesis(16).In rats (13),whereasCCKandPYYremained /Finalversionofthemanuscript increased theexpressionofFAT/CD36(fatty parameters has stronginfluenceonnutrient ogether, theseresultssuggestthatOEAplaya adipocytes,OEAinducedanincreaseofthe uggest thattheincreased fattyaciduptakein monstrating thattheeffectonbodyweightis not imply the modulation ofthesecretion so toadirecteffectonlipidmetabolism (4). 1 thatisexpressedinpreadipocytes.Once studies arenecessarytoconfirm thatOEA 10.1007/s11745-008-3217-y suggesting anincreasedlipolysis(7),itis a higherreductionofbodyweightgain effect wastestedon 6 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 171 170 169 168 167 166 165 164 163 162 161 160 159 158 157 156 155 154 153 152 151 150 149 148 147 172 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, a potentendogenousPPAR- been performed, inwild-typeandPPAR- ligands ofPPAR- α (4) aremediated bytheactivationofperoxisome 1.3. Oleoylethanolamide(OEA)actsperipherally trials. mature adipocytes.Theseresultswouldhave increased lipid (18). Consequently,themajor actionofOEAonlipidmetabolism wouldbeessentiallyan the localactionofOEAonpreadipocytesdi inflammatory analoguepalmitoylethanolamide (P after thenegativecontrolof norleptinneitherPPAR- Nevertheless, OEAconcentrationwasnotd adipogenesis inadiposetissue(16)andtheactivationoflipid cholesterol andtriglyceridelevels(10). reduced theaccumulation oflipiddropletsin a studyperformed onPPAR- demonstrated modulation ofFAT/CD36expression(7).Thes and, simultaneously increasingfattyaciduptak would playanimportant roleinlipidmetabo the utilizationofnutrientinsmall intes published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans ) (19)witharelativelyhighaffinity(Kd It hasbeendemonstrated thatsome of These resultssuggestthatOEAhaslipol in-vivo β -oxidation inmuscle andabetterfat α presentinpartiallydigested foodsuchasfreefattyacids(20).Astudyhas 1-8. DOI: 10.1007/s11745-008-3217-y , suggestingaroleofPPAR- Comment citer cedocument: α α agonist,canregulatefood inta nullmice (17),butalsoinobeserats,asOEAtreatment can

α = 37.4nM)compared tootherpotentialendogenous knock-outmice, tounderstandhow OEA,whichis tine. ThesefindingssupportthefactthatOEA fferenciation throughtheactivationofTRPV1 ecreased duringpreadipocytesdifferenciation lism byincreasing thelipolysisinadipocytes /Finalversionofthemanuscript the OEAobservedperipheralanorexiceffects to beconfirmed inhumans throughclinical proliferator-activatedreceptoralpha(PPAR- α EA) (16).Theselast 10.1007/s11745-008-3217-y liverandsignificantlydecreaseplasma infatty acid ytic propertiesthroughtheinhibitionof e resultsonlipolysiswerepreviously e inintestine,partiallyimplicating the utilization throughahigherlipolysisin γ , contrarytothelevelof itsanti- ke andbodyweightgain (10). β -oxidation inmuscle through β -oxidation inmuscle (17). findings donotfavour 7 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 190 189 188 187 186 185 184 183 182 181 180 179 178 177 176 175 174 173 193 198 197 196 195 194 192 191 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, between theratTRPV1receptora (22, 24).Anotherstudywasperformed group butnotinTRPV1-nullgroup,showingthero injected withOEA(12.5mg/kg bw).Short-term TRPV1 involvement inOEAeffectsonfood by theproteinkinaseC,itbecomes more and theexcitationofsensorynervesexpre a roleonfoodintakecontrol.OEAwasshown chemicals andthermal stimuli, andinvisceral expressed inbothnociceptiveneurons,where peripheral vagalsensorynervesinvolvedinthe in human celllinesexpressingTRPV1(22).TR perivascular sensorynervesandelicitswholecellcurrentsfluorometric calcium response TRPV1. Atsubmicromolar concentrations, confirmed with some mutant mice (10).This implication ofPPAR- plasma cholesterol levelsinwild-typemice, This studyshowedthatOEAreducesfoodinta TRPV1 islinkedtoaCa published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans and pancreaticcells(26, 27).Thisreceptorisma activates GPR119withan EC vagal sensorynerves,and,consequently,onfood intakeregulation. stopping TRPV1 receptor-transfectedcells.OEAshow In additiontoitsinteractionwithPPAR- Furthermore, aprotein-Gcoupledrecepto 45 Ca 2+ uptakeincellsexpressingTRPV1(25).Themechanism ofactionOEAon 1-8. DOI: 10.1007/s11745-008-3217-y in-vitro Comment citer cedocument: 2+ concentrationmodulation insidethecell,inducinganeffect on genereporterassaysoncellcultures(21). 50 superiorto30µM),has been

nd OEA,employing measurement of ssing TRPV1.Indeed,ifTRPV1isphosphorylated in-vivo whereas itdoesnothavesucheffectsinPPAR- sensoryneuronsandbrain,whereitcouldhave sensitive toOEAactivation(23).Toconfirm OEA activatesnativeTRPV1inrodentson α /Finalversionofthemanuscript ed agonistpropertiesonTRPV1receptorby take, normal mice andTRPV1-nullmice were nervous controloffoodintake(23).TRPV1is inOEAmechanism ofactionhasalsobeen α to indirectlyregulatetheactivityofTRPV1 feeding wassignificantlyreducedincontrol r (GPR119)havingaffinity withOEA(OEA it isinvolvedinthedetectionofnoxious and 10.1007/s11745-008-3217-y , OEAhasbeenshowntobeanagonistof ke, inhibitsbody-weightgainandlowers inly expressedinthegastrointestinal tract PV1 activationleadstotheexcitationof le ofthisreceptorinfeedingregulation in-vitro recently identifiedinintestinal toestablishtherelationship 45 Ca 2+ uptakein α 8

Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 207 206 205 204 212 211 210 209 208 203 202 201 200 199 223 222 221 220 219 218 217 215 214 213 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, OEA) (19,29).OEAcanactivateintestinalPPAR- proposed. FattyacidsandderivativessuchasOEAarePPAR- OEA (28). cells. Thismechanism wouldmodify theelectricalstatusofCa addition tothisintestinaleffect, circula expression modulations wouldbeinvolvedinf response elements, leadingtotheactivationof receptor suchasRXR.Indeed,PPAR- regulation hasbeendemonstrated, itiss satietigenic effects(26).However,althoughtheimplication ofGPR119infoodintake to GPR119activation.Asisactivatedby administration (100mg/kg bw). Itinduceda30% The satietogenicefficiencyofPSN632408wasinvestigated and inthepancreas.Aspecificagonist effect onglucosetolerance onshorttime ratherthanadiabetogeniceffect(31). significant differencesin anyothertime points animals hadsignificantlyhigherplasma glucos management weretested control withoutdecreasingtheinsulinlevel( 1.4. Effectsofoleoylethanolamide(OEA)onglucosemetabolism food intakeregulation. 216 depolarization (24).Thus,thevagalsensoryne published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans In Rats, intraperitoneallytreatedwithOEA, Figure 1 , atentativemechanism ofactionOEAonthecontrolfoodintakeis 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument: in-vivo byperforming glucosetolerancetests(31).OEA-treated

α of GPR119,named PSN632408,hasbeenidentified. ting OEAcouldblockTRPV1receptoronneuronal andRXRcanform anhete till uncertainwhetheritcanbeactivated 31). TheeffectsofOEAontheplasma glucose /Finalversionofthemanuscript ood intakeandlipidmetabolism regulation.In e after30min ofglucoseload,butnoother rves wouldbeexcited,influencingdirectly targetgenestranscription(29,30).These have beennoticed,indicating animpairing decrease offoodintake,stronglyassociated 10.1007/s11745-008-3217-y showed aglucoseintolerancecompared to OEA, itcouldpartiallyparticipatetoOEA α inducingtheactivationofothernuclear in-vivo α ligands(Kd=37.4nMfor 2+ rodimer thatcanbindto throughintraperitoneal channel inducingsmall in-vivo by 9 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 249 248 247 246 245 244 243 242 241 240 239 237 236 235 234 233 232 231 230 229 228 227 226 225 224 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, with aphosphatidicacid molecule, is rel molecular N-acylationfrom PE,PC,lyso-PCorcardiolipin ( proposed fortheformation of phosphatidylcholine (PC)toaphosphatidylethanolam step, catalyzedbyNAT,consiststothe acyl-phosphatidylethanolamine phospholipaseD(NAPE-PLD) ( steps, whicharecatalyzedby observed inadiposetissueandinsulinoma such asenterocytes(brushborder)(32-40),ne 2. METABOLISMOFOLEOYLETHANO 238 would havetobeperformed includingaglucosetolerancetestonhepaticcells. to bemediated byphosphorylationanddephosphor insulin-stimulated glucosetransport(31).Indee the glucosetransporterGLUT4,whichcouldc level atanytime point(10),andithasbeen Moreover, inanotherstudy,OEAadministration adipocytes, theliverandskeletalmu and, ontheotherhand,onlypartofglucoseclearancefrom thebloodhappensin because, ononehand,theglucosetransportinhibiti observation cannottotallyexplaineth inhibition ofinsulin-stimulated glucoseuptakeandinhibitsinsulinaction(31).These published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans In mammalian tissue,thesynthesis/degradationof OEAoccursmainly inspecific cells OEA effectsonglucosemetabolism seem to Some experiments performed onisolated ad 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument: two differentenzymes named N -acyl-phosphatidylethanolamine (NAPE) byinter-orintra-

e glucoseintoleranceobservedinrats N -acylation ofanoleicacidresiduefrom membrane eased from theNAPEformed byNAPE-PLD- reported thatOEAcantr scle stronglycontributetothisphenomenon. LAMIDE (OEA)INANIMALS ounter-balance theobservedOEAinhibitionof /Finalversionofthemanuscript d, glucosetransportactivityhasbeenreported β vertheless, OEAbiosynthesishasalsobeen -cells (41).OEAbiosynthesisinvolvestwo did notinducemodification ofbloodglucose 10.1007/s11745-008-3217-y ylation oftransporterssuchasGLUT4. on duetoOEAinadipocytesisreallylow, ipocytes showedthatOEAinducesa30% ine (PE).Differentpathwayshavebeen dependonthetissue,furtherstudies N Figure 3 -acyltransferase (NAT)and Figure 2 igger phosphorylationof ) (43).OEA,together ) (42,43).Thefirst in-vivo (31), N 10 - Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 261 260 259 258 257 256 255 254 253 252 251 250 274 273 272 271 270 269 268 267 266 265 264 263 262 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, degradation (45). in themucosa ofproximal intestinethroughaconcertedregulationofOEAbiosynthesisand hydrolase (FAAH)activityandexpression.Nutrie and jejunum byincreasingNAPE-PLDactivityandexpressiondecreasingamido- al. like-protein isamore ubiquitousamidase ( degradation accordingtohighlevelsofpl like-protein) (44).FAAHisspecificforfatty Acid Amide Hydrolase(FAAH)orN-Acyls OEA canbebrokendownintooleicacidandet catalyzed hydrolysis.Alternatively,hydrolysis published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans caracterised byahigher OEA levelintheirplas OEA biosynthesisisactivated byglucoseandinsulin(41).Inaddition, diabete IIpatientsare OEA levelsaredecreasedunder“highglucose” variate duringdifferenciationcontraryto about theregulationofOEAsynthesisinothe OEA. with OEA compared and gutmorphology. fasting. Theirwayoffeedingseems todependon observed inBurmese pythons( (45),indeedfeedingstimulates OEAmobilization inthemucosal layerofratduodenum Astarita Moreover, thelinkbetweenOEAandfoodintakeregulationhasbeenshownbyFu OEA synthesisintheintestinalmucosa

to fastedanimals hasbeenobserved(2 in-situ et al , thereforeNAPEscanbeconsidered 1-8. DOI: 10.1007/s11745-008-3217-y

. (2)examined whetherfeeding-induced A nearly300-fold Comment citer cedocument: Python molurus),

increase inOEAlevelsthesmall intestineof fed Figure 4 PEA levels(41),whereas,ininsulinoma β asma OEA inFAAH-nullmice (15),andASAH phingosine Amidohydrolase likeprotein(ASAH /Finalversionofthemanuscript hanolamine by twodifferenthydrolases:Fatty acid amides andmainly responsibleofOEA canbecatalyzedbythephosphodiesterase. ma afterfoodconsumption (41).Alltogether, conditions (41).In“highglucose”conditions, r tissues.Inadipocytes,OEAlevelsdonot

has beenextensivelystudied,lessisknown

which consumes hugemeals changes ingastrointestinalhormonal release nt availabilityregulatesOEAmobilization 10.1007/s11745-008-3217-y ). NAPEspeciesincreasesimultaneously ) (42). as potentialbiosyntheticprecursorsfor

OEA mobilization canbe

after months of -cells, et 11 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 290 289 288 287 286 285 284 283 282 281 280 279 278 277 276 275 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, necessary. in weightmanagement isimportant andstudies been extensivelystudiedtodate.Thegapbetw the effectsofchronicoraladministration of lipid storageinliverandcirculatingplasma lip through activationofperipheralPPAR- gastrointestinal tract.Thecorebiologicalfunc ethanolamine bytheFAAHorASAH-like PLD. Afteringestion,OEAhasashortlife-time andiscleavedintoacidoleic endogenous signalinglipidformed from PEa CONCLUSION ANDPERSPECTIVES (41). these resultssuggestthatOEAbiosynthesis published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans OEA isaverypromising molecule, simple derivativeofoleicacid,isatransient 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument:

α , 2)topromote lipidutilization,and3)tomodulate

OEAonlipidmetabolism andsatietyhavenot is downregulatedundertransienthyperglycemia nd PCthroughtheactionsofNATandNAPE- /Finalversionofthemanuscript een thescienceandpotentialapplications tions ofOEAare1)tocontrolfoodintake ids (triglyceridesandcholesterol).However, evaluatinglong-term effectsandsafetyare 10.1007/s11745-008-3217-y protein inmany tissues,includingthe 12 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 322 321 320 319 318 317 316 315 314 313 312 311 310 309 308 307 306 305 304 303 302 301 300 299 298 297 296 295 294 293 292 291 290 338 337 336 335 334 333 332 331 330 329 328 327 326 325 324 323 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, 10. Gaetani,S.,Oveisi,F.,andPiomelli, D.(2003)Modulationofmeal patternintherat 9. Proulx,K.,Cota,D.,Castaneda,T.R.,Tschop,M.H.,D'Alessio, D.A.,Tso,P., 8. Yang,Y.,Chen,M.,Georgeson,K.E.,andHarmon, C.M.(2006)Mechanism of 7. Kirkham, T.C.,Williams, C.M.,Fezza,F.,andDiMarzo,V.(2002) 6. Petersen,G.,Sorensen,C.,Schmid, P.C.,Artmann, A.,Tang-Christensen,M., 5. RodriguezdeFonseca,F.,Navarro,M.,Gomez, R.,Escuredo,L.,Nava,F.,Fu,J., 4. DiMarzo,V.,Sepe,N.,DePetrocellis,L.,Berger,A.,Crozier,G.,Fride,E.,and 3. Astarita,G.,Rourke,B.C.,Andersen,J.B.,Fu,J.,Kim, J.H.,Bennett,A.F.,Hicks, 2. Lambert, D.M.,Vandevoorde,S.,Jonsson,K.O.,andFowler,C.J.(2002)The 1. REFERENCES published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans 4 Aviello,G.,Matias, I.,Capasso,R.,Petrosino,S.,Borrelli,F.,Orlando,P., Romano, 14. Cani,P.D.,Montoya,M.L.,Neyrinck,A.M.,Delzenne,N.andLambert, D.M. 13. Oveisi,F.,Gaetani,S.,Eng,K.T.,andPiomelli, D.(2004)Oleoylethanolamide 12. Nielsen,M.J.,Petersen,G.,Astrup,A.,andHansen, H.S.(2004)Foodintakeis 11. 1311-1316 by theanorexiclipidmediator oleoylethanolamide. Neuropsychopharmacology Physiol changes infeedingbehaviorandmotor activity.AmJPhysiolRegulIntegrComp Woods, S.C.,andSeeley,R.J.(2005)Mechanisms ofoleoylethanolamide-induced body weightreduction. acylethanolamides (OEA)onfattyaciduptake Pharmacol feeding andsatiation:stimulation ofeatingby2-arachidonoylglycerol. Endocannabinoid levelsinratlimbic forebr their precursors. of anandamide andoleoylethanolamide infood-deprivedratsareregulatedthrough Hansen, S.H.,Larsen,P.J.,Schmid, H.H.,andHansen,S.(2006)Intestinallevels 209-212 and Piomelli, D.(2001)Ananorexiclipidmediator regulatedbyfeeding. Murillo-Rodriguez, E.,Giuffrida, A.,LoVerme, J.,Gaetani,S.,Kathuria,Gall,C., 637 Mechoulam, R.(1998)Trickortreatfrom Nature396,636- foodendocannabinoids? Comp Physiol in small intestine oftheBurmese python(Pythonmolurus). W., andPiomelli, D.(2006) Postprandial Chem palmitoylethanolamide family: anewclassof anti-inflammatory agents? Mol Med compound oleoylethanolamide ongastricemptying incontroland overweight mice. B., Capasso,F.,DiMarzo, V.,andIzzo,A. oleoylethanolamide. anorexigenic cannabinoidcompounds, SR141716A(rimonabant) and (2004) Potentialmodulation ofplasma ghrelinandglucagon-likepeptide-1by 461-466 inhibits foodintakeinfree-feedingratsafteroral administration. inhibited byoraloleoylethanolamide. rats. Neuropharmacology endogenous PPAR-alphaagonist,lowersbodyweightandhyperlipidemia inobese Fu, J.,Oveisi,F.,Gaetani,S.,Lin,E.,andPiomelli, D.(2005)Oleoylethanolamide, an 9,663-674 289,R729-737 86,413-422 136,550-557 1-8. DOI: 10.1007/s11745-008-3217-y 290,R1407-1412 Comment citer cedocument: Biochim BiophysActa Br JNutr Am JPhysiolRegulIntegrComp 48,1147-1153

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282,1518-1528 /Finalversionofthemanuscript 10.1007/s11745-008-3217-y 16 Version postprint Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript Manuscrit d’auteur / Author manuscript 451 450 449 448 447 446 445 444 443 F., Destaillats, F.(2008). Biologicalfunctions andmetabolism ofoleoylethanolamide. Lipids, Thabuis, C.,Tissot-Favre, D.,Bezelgues, J.-B.,Martin, J.-C.,Cruz-Hernandez, C., Dionisi, Figure 4. Figure 3. Schmid (43)]. Figure 2. Potential Vanilloid1. respectively forPeroxisome ProliferatorActivatedReceptor Figure 1. Legend ofFigures. published in:Lipids,2008,OnlineFirst,DOI: Version définitivedumanuscritpubliédans Catabolism ofoleoylethanolamide (OEA),adaptedfrom LoVerme Inter-andintra-molecular N-acylationof PE Metabolism of oleoylethanolamid Mechanism ofactionol 1-8. DOI: 10.1007/s11745-008-3217-y Comment citer cedocument:

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