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M. noanbnisi ohfo naeadoeiy wn olmtdsae eetreviews recent papers. space, and original the limited of biosynthesis of to instead involvement Owing the cited obesity. the for often and of be mechanisms intake analysis will the food brief both a about in with known endocannabinoids together currently endocannabinoids, is of what inactivation of overview an ellrutk r tl ujc fdbt.Mroe,ltl sytkonaotteroles the about known yet is their little in Moreover, involved debate. by processes of from the degradation subject derived endocannabinoids a characterised, intracellular of still metab- well their and are been biosynthesis uptake in have the cellular for culminates endocannabinoids extra- responsible the of and from the olism transport space Although their oxidation. with intracellular or begins hydrolysis the that process to two-step a cellular via inactivated Endocannabinoids and conditions. cells pathological and mainly physiological are both in system cannabinoid edcnaiod)ado h isnhtcadmtblcezmso h endocannabi- the of agonists enzymes endogenous metabolic their and of biosynthetic receptors, signi the cannabinoid noids, of of discovery and the (endocannabinoids) from on Following ( 9 ( . ) α 7 te noanbnismgtbe might endocannabinoids Other . https://doi.org/10.1017/S0029665113003418 / , β ‘ 8 nnaie -rcioolgyeo:Cnaiodrcpos oditk:Obesity intake: Food receptors: Cannabinoid 2-arachidonoyl-glycerol: Anandamide: 1 ) oynauae at cdmdaos mlctosfrhmnhealth human for implications mediators: acid fatty Polyunsaturated hdoaedmi;2A,2aahdny-lcrl O,ccoxgns-;DG,daygyeo iae DHEA, ; diacylglycerol DAGL, cyclooxygenase-2; COX, 2-arachidonoyl-glycerol; 2-AG, domain; -hydrolase UAdrvdedcnaiod:a overview an endocannabinoids: PUFA-derived n oitrc with interact to and , n CB and ypsu :Cnaiod nhmnhealth human in 3: Symposium . 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( 31 20 15 N ) ) ) - . . , ’ taoaieb calcium-dependent a of by formation phosphatidyl- ethanolamine pathway (1) from process: biosynthetic (NAPE) two-step phosphatidyl-ethanolamine main a the of Both neur- consists anandamide, pathways. post-synaptic in For at metabolic ons. produced differences and are biochemical some endocannabinoids of exhibit terms endocannabinoids structure, in similar locally. these are mainly 2-AG and receptors anandamide cannabinoid Although target to released the for occur can routes pathways similar that metabolic probably the is for and it studied largely biosynthetic been have the Although napoesta sctlsdb AEhdoyigphos- NAPE-hydrolysing D by catalysed pholipase is that N-acylethanolamines process form a to in NAPE of hydrolysis (2) and lentv ahashv enproposed been anandamide, have synthesise pathways to alternative able also are D stocoeyrltdgnsdesignated related closely two as nteCB the on paetylssteaiiyt edrce oad the towards directed be to compartment ability lysosomal the loses apparently lcrllps DG)o h rcioi acid- arachidonic the of 2-AG to arachidonic (DAGL) DAG containing containing lipase phospholipids glycerol phospholipase by the inositol at hydrolysis acid of of consists C 2-AG for way in summarised are nldvlpet oaiaino DAGL of neur- localisation during development, that onal revealed have studies Pharmacological cannabinoid of debate type of subject third a a still is of GPR55, receptor, existence the Finally, CB the Whether hlseo otn;ide,mmrn cholesterol lines cell CB to immortalised membrane binding and the primary reduces indeed, both in enrichment content; cholesterol lotrcbnigst,wrat ute investigation. further warrants CB site, Cannabinoid binding allosteric modi tdwt pca ebaemcooan,named microdomains, membrane special ‘ with ated eesdatrcl tmlto,btisedthey instead but phospholipids stimulation, membrane from be formed cell to rapidly waiting are after neurotransmitters classical released as in stored such not cells are Endocannabinoids endocannabinoids. demand n ieta a ercgie ysnhtcsalmol- small synthetic the by for recognised reported be was can ecules that site ing nmcola srctsadi eta neurons central in and detected been astrocytes also , have they in recently and cells, immune xnltat nteeby odendritic to embryo from i.e. the elements, in post-synaptic tracts to axonal pre- from changes rcse uha onto,mmr,mtrfunction motor memory, cognition, analgesia brain and as in control pathways such endocannabinoids areas pain processes these the In in cord. as spinal and well nucleus as entopeduncular pallidus, and globus reticulate, pars ALwscoe n ute characterised further and cloned was DAGL ii rafts lipid , subjectto theCambridgeCore termsofuse,available at fi saadmd-nue noyoi fCB of endocytosis anandamide-induced es noanbnisboytei n uptake and biosynthesis Endocannabinoids ’ hr n hnnee,adimmediately and needed, when and where , 1 ’ sn ( 33 anbni eetr fa lotrcbind- allosteric an of receptors cannabinoid ( 2psto n ute yrlssb diacyl- by hydrolysis further and position -2 38 ) ( 32 hsascaini ral fetdby affected greatly is association This . – 40 ) nieCB Unlike . ) 2 2 eetr uha CB as such receptor, ( i.1 Fig. i.1 Fig. eetr r anyepesdin expressed mainly are receptors ( 33 h anboytei path- biosynthetic main The . 1 .SneclslcigNAPE- lacking cells Since ). ) ( nta hlseo depletion cholesterol instead ; 48 motnl,teexistence the Importantly, . 2 ) fi ,CB s ieb u group our by time rst ( i.2 Fig. n 1 6endocannabinoids, -6 eetr r associ- are receptors .I 03 human 2003, In ). 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DAG, PLC https://www.cambridge.org/core β α β koku mice -knockout koku nml xiie ihrno either exhibited animals -knockout koku ieso akd(pt 80%) to (up marked show mice -knockout NArPE ceai ersnaino nnaiead2aahdny-lcrlboytei ots E,aadmd;NAPE, anandamide; AEA, routes. biosynthesis 2-arachidonoyl-glycerol and anandamide of representation Schematic α ( ly nesnilrl nterglto fret- of regulation the in role essential an plays 49 Phospho-AEA , 50 2-lyso- Abhd4 ) utemr,svrlsuissuggest studies several Furthermore, . ( 52 O O ) . H N https://doi.org/10.1017/S0029665113003418 PLA H N N 1 nban2A ees 2 several (2) levels; 2-AG brain in -arachidonoyl-PE eetr oidc rnin sup- transient induce to receptors ( 51 2 – 2 53 hshlps A phospholipase , O . IPaddress: α O ) RO koku,btntin not but -knockout, ieaadmd,also anandamide, Like . 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M. ca- fi ) ) - . . iaeadFA ciiyadicesdNAPE- increased and activity action FAAH D diets phospholipase and monoacylglygerol high-fat decreased endocan- lipase to the due of Thus, probably levels the nabinoids, modulate and system. motility can intestinal in intake increase endocannabinoid reported dietary that data the suggest several literature Indeed, the disorders. metabolic n eihrltsus n hleg o st develop: physiological to central CB is several restricted now both peripherally new challenge in (a) in One tissues. conditions role peripheral and pathological crucial endocannabinoid and the a that processes plays accepted generally system now is It itsol ecniee ihcuini newborn in phos- brain caution function in and alterations with composition long-lasting pholipid cause considered can it be since should diet None. article. this of writing role or a analysis had Otsuka design, or the Pharmaceuticals in Otsuka. GW and from Pharmaceuticals one GW No by provided was This advice. and support (University continuing Pertwee his G. for Roger Aberdeen) Professor of thank to wish I to hypertension as, sclerosis, such cancer. multiple disorders, pain, and of few, range a a just recep- of mention their treatment at the endocannabinoids for of tors level tissue the affect blood the cross hthv enosre ihdrc CB direct with side-effects observed unwanted been sought-after the have show the that not maintaining do effect while therapeutic that antagonists or frcpo stimulation receptor of e assadces nNP-hshlps ,FAAH also D, marked NAPE-phospholipase but a in CB biosynthesis, and decrease to a endocannabinoid contributes causes only in DHA, not phospho- and decrease from membranes, acid EPA arachidonic displace of lipid widely to able intake been are increased that has Indeed, biosynthesis studied. endocannabinoid lating dietary noanbni oei bst ih et use to 2-AG be in reduction might consequent obesity biosynthesis with inhibitors in DAGL tone endocannabinoid fi , subjectto theCambridgeCore termsofuse,available at ili rvnigteosto ohoeiyadother and obesity both of onset the preventing in cial fi 1 hoil sh RAepeso ihacneun reduction consequent a with expression mRNA ocuin n uuedirections future and Conclusions ( 106 ) n ial,cagsi itcnb ben- be can diet in changes Finally, . – 3ftyais P n H,i modu- in DHA, and EPA acids, fatty -3 ri are;()nwmdcnsthat medicines new (b) barrier; brain Con Acknowledgements iaca Support Financial fl ( 107 cso Interest of icts ( 107 ) oee,sc hnein change a such However, . ) neetnl,terl of role the Interestingly, . 1 eetraoit and/ agonists receptor ( 105 ) . 1 iad which ligands https://www.cambridge.org/core/terms Downloaded from Proceedings of the Nutrition Society 0 au ,Abu-La L, Hanus 10. 3 ePtoelsL trwc ,Mrel AS Moriello K, Starowicz L, Petrocellis De 13. 2 ePtoelsL acoM iMroV(04 The (2004) V Marzo Di & MG Cascio L, Petrocellis De 12. 7 uir ,KnoS uaaaA Sukagawa S, Kondo T, Sugiura 17. drugs of potential therapeutic The (2005) RG Pertwee 14. 5 rw ,Csi G al KWJ Wahle MG, Cascio I, Brown 15. 1 otrA,SurJM nemnMD Knierman J-M, Sauer AC, Porter 11. 6 ion ,Dlo adnruk ,Mln A Milone I, Vandenbroucke Delton T, Bisogno 16. .SglE arR ázI Rácz R, Baur E, Sigel A 9. Sukagawa S, Kondo T, Sugiura 8. .McolmR e-hbtS au L Hanus S, Ben-Shabat R, Mechoulam 7. RA Ross KN, Wease A, Al-Hayani 6. JC Jerman MJ, Gunthorpe D, Smart 5. A Breuer L, Hanus WA, Devane 2. .D az ,BsgoT&D ercli (2001) L Petrocellis De & T Bisogno V, Marzo Di 4. anandamide of isolation and Discovery (2007) LO Hanus 3. .D az ,BfloM&D ercli 20)The (2004) L Petrocellis De & M Bifulco V, Marzo Di 1. lcrlehr nedgnu gns ftecannabinoid the of agonist CB endogenous an ether, glyceryl euaino rnin eetrptnilcanl of cannabinoid channels cAMP, of potential CB effect (TRPM8): receptor 8 type transient melastatin of Regulation noanbni ietyat tGB()receptors. USA GABA(A) Sci at Acad Natl acts Proc directly endocannabinoid brain. in Commun cannabi- receptor receptors. endogenous noid cannabinoid possible a to 2-arachidonoylglycerol: binds that slice. gut, Pharmacol Biochem canine hippocampal in rat Identi the activates in anandamide Neuropharmacology receptors cannabinoid vanilloid endogenous The noanbni ytm eea iwadlatest and view general a additions. system: endocannabinoid noeoslpdaadmd safl gns tthe at agonist full (hVR1). a 227 receptor is vanilloid anandamide human lipid endogenous hot. 346 it like some Anandamide: the 1841. endocannabinoids. to other binds and that constituent brain a receptor. cannabinoid of structure and ie ihatgns ciiya h B receptor. CB1 the at activity Ther Exp Pharmacol antagonist virodha- J endocannabinoid, with novel mine, a of Characterization a e rgDiscov Drug exploitation. Rev therapeutic Nat its and system endocannabinoid u anbni eetrlgn,adrltdlpdmol- tissues. lipid nervous 14 related the and in ligand, ecules receptor cannabinoid ous endogen- an (anandamide), N-arachidonoylethanolamine tissue endocannabinoids. the of modulate actions or or receptors levels cannabinoid target that e eetrpstv n ngtv rsaecne cell cancer prostate -negative andro- lines. and in receptor-positive ethanolamides omega-3 gen of anti- effects -independent proliferative and receptor-dependent Cannabinoid E654. 1911 ehnlmn nbvn . 370 bovine in lethanolamine N-docosahexaenoy- and (anandamide) noylethanolamine al et https://www.cambridge.org/core ,51 1 1 – – 300 , 19)Boytei n nciaino N-arachido- of inactivation and Biosynthesis (1999) . 230. 349. – receptor. eetr n endovanilloids. and receptors fi 1920. Carcinogenesis – aino nedgnu -oolcrd,present 2-, endogenous an of cation 56. – 215 307. rJPharmacol J Br ,89 rcNt cdSiUSA Sci Acad Natl Proc – . fi 97. https://doi.org/10.1017/S0029665113003418 ,FieE Fride S, References 41 50 31 3 Science 1000 , ,83 771 , 1584 , 301 tal et 108 . IPaddress: – 1020 , 141 90. – – 18150 , 784. – ii eitCl Signal Cell Mediat Lipid J 1005. 21)Temjrcentral major The (2011) . 765 , 258 1591. tal et hmBiodivers Chem rnsPamclSci Pharmacol Trends – rhBohmBiophys Biochem Arch 1946 , 1024. ice ipy Res Biophys Biochem tal et 20)2-arachidonyl (2001) . 170.106.203.74 – rJPharmacol J Br – 774. x elRes Cell Exp 18155. ASJ AAPS 19)Isolation (1992) . tal et – 98 1949. 3662 , tal et tal et tal et tal et UAdrvdedcnaiod 457 endocannabinoids PUFA-derived tal et tal et 20)The (2000) . tal et , on 4 7 (1995) . (1996) . (2010) . (2001) . – (2002) . (1995) . 1828 , E625 , (2007) . 06 Oct2021 at16:09:57 3665. 129 313 22 – – , , , 4 rc R ali L hmsA Thomas GL, Baillie MR, Price 34. 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