Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

Abstract

The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications. The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications. arachidonic acid N-arachidonoylethanolamine 2-arachidonoylglycerol cannabinoid receptor docosahexaenoic acid docosahexaenoylethanolamine 2-docosahexaenoylglycerol eicosapentaenoic acid 2- eicosapenaenoylglycerol oleoylethanolamine 2-oleoylglycerol The endocannabinoid system includes two G-protein coupled cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids), and the enzymes and transporters that help regulate cannabinergic tone (1De Petrocellis L. Di Marzo V. An introduction to the endocannabinoid system: from the early to the latest concepts.Best Pract. Res. Clin. Endocrinol. Metab. 2009; 23: 1-15Crossref PubMed Scopus (189) Google Scholar). Endocannabinoid signaling is ubiquitous in mammals, being particularly critical in brain, where it modulates neurotransmitter release and exhibits neuroprotective effects (2Kano M. Ohno-Shosaku T. Hashimotodani Y. Uchigashima M. Watanabe M. Endocannabinoid-mediated control of synaptic transmission.Physiol. Rev. 2009; 89: 309-380Crossref PubMed Scopus (1117) Google Scholar, 3Hwang J. Adamson C. Butler D. Janero D.R. Makriyannis A. Bahr B.A. Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality.Life Sci. 2010; 86: 615-623Crossref PubMed Scopus (71) Google Scholar). Although the first two endocannabinoids identified, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (AG), have been extensively characterized, the (patho)physiological impact of endocannabinoid signaling has prompted the search for additional endocannabinoids and their related metabolites/biosynthetic precursors, creating an evolving network of chemical species collectively termed the endocannabinoid metabolome, few of which have been functionally annotated (1De Petrocellis L. Di Marzo V. An introduction to the endocannabinoid system: from the early to the latest concepts.Best Pract. Res. Clin. Endocrinol. Metab. 2009; 23: 1-15Crossref PubMed Scopus (189) Google Scholar, 3Hwang J. Adamson C. Butler D. Janero D.R. Makriyannis A. Bahr B.A. Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality.Life Sci. 2010; 86: 615-623Crossref PubMed Scopus (71) Google Scholar, 4Bradshaw H.B. Walker J.M. 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Bahr B.A. Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality.Life Sci. 2010; 86: 615-623Crossref PubMed Scopus (71) Google Scholar, 9Kingsley P.J. Marnett L.J. Analysis of endocannabinoids, their congeners and COX-2 metabolites.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2009; 877: 2746-2754Crossref PubMed Scopus (24) Google Scholar). Defining the extent to which specific dietary components can modulate the physiological endocannabinoid metabolome has been highlighted as an important contemporary research goal (10Janero D.R. Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.Expert Opin. Emerg. Drugs. 2009; 14: 43-65Crossref PubMed Scopus (163) Google Scholar, 12Artmann A. Petersen G. Hellgren L.I. Boberg J. Skonberg C. Nellemann C. Hansen S.H. Hansen H.S. 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The for oleoylethanolamine plasma brain the brain plasma of by the the glycerol-ester endocannabinoid metabolome constituents dietary influence brain plasma of 2- of and 2-oleoylglycerol in brain in plasma. the of in the 2-eicosapentanoylglycerol markedly in both brain and plasma. the two principal endocannabinoids in mammalian and are derived from the fatty acid, (1De Petrocellis L. Di Marzo V. An introduction to the endocannabinoid system: from the early to the latest concepts.Best Pract. Res. Clin. Endocrinol. Metab. 2009; 23: 1-15Crossref PubMed Scopus (189) Google Scholar, 3Hwang J. Adamson C. Butler D. Janero D.R. Makriyannis A. 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The ability of dietary DHA enhancement to select constituents of the physiological endocannabinoid metabolomes of brain and plasma has metabolic and therapeutic implications. a for to the short-term effects of DHA on endocannabinoid-related lipid species and of and health.