Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency

Abstract

Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of G i/o protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2-deficient ( fads2 −/− ) mouse, deficient in LC-PUFA synthesis, to follow the age-dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained LC-PUFA-free ω6-arachidonic acid- and DHA-supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis -5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:3 5,11,14 -ethanolamide and 2-20:3 5,11,14 -glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded Δ8-desaturase activity and proved the position specificity of FADS2. The fads2 −/− mutant might serve as an unbiased model in vivo in the development of novel CB1 agonists and antagonists.

Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids

“…Association studies on nucleotide polymorphisms in the FADS locus in humans show important differences in the capacity of different populations to synthesize LC-PUFAs including AA [ 48 ]. Recently, in an auxotrophic Δ6 desaturase deficient (fads2 -/-) mouse lacking LC-PUFA synthesis, an impact on the precursor pool of ECs through transformation of eicosa-all cis-5,11,14-trienoic acid into two novel ECs, 20:35,11,14-ethanolamide and 2–20:35,11,14-glycerol was reported [ 49 ], thus indicating PUFA plasticity in mammals.…”

Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle

“…Both LCPUFA are also involved in the formation of endocannabinoids (eCB) with regulatory effects at the central nervous system (CNS) [ 114 ]. The endocannabinoid system consists of eCB, eCB receptors CB1 and CB2, and associated anabolic and catabolic enzymes [ 115 ]. Their functions are to maintain body energy homeostasis through the nutrient availability detection and the modulation of orexinergic inputs in selective regions of the CNS [ 116 ].…”

“…Their functions are to maintain body energy homeostasis through the nutrient availability detection and the modulation of orexinergic inputs in selective regions of the CNS [ 116 ]. PUFA derived eicosanoids and eCB have been identified as independent ligands of CB1 and CB2 receptors [ 115 ]. Hammels et al (2019) [ 115 ] reported that CB1 ligands synthesis in CNS depends on dietary intake of AA and DHA in a model of fatty acid desaturase 2-deficient mouse [ 115 ].…”

“…PUFA derived eicosanoids and eCB have been identified as independent ligands of CB1 and CB2 receptors [ 115 ]. Hammels et al (2019) [ 115 ] reported that CB1 ligands synthesis in CNS depends on dietary intake of AA and DHA in a model of fatty acid desaturase 2-deficient mouse [ 115 ]. Moreover, DHA and AA have been recognized as ligands of the nuclear RxR receptor in the brain, being the PUFA ratio in the western diet, a critical nutritional parameter for numerous neurodegenerative diseases [ 115 ], which could increase neuroinflammation and over-stimulation of the endocannabinoid system [ 117 ].…”

“…Hammels et al (2019) [ 115 ] reported that CB1 ligands synthesis in CNS depends on dietary intake of AA and DHA in a model of fatty acid desaturase 2-deficient mouse [ 115 ]. Moreover, DHA and AA have been recognized as ligands of the nuclear RxR receptor in the brain, being the PUFA ratio in the western diet, a critical nutritional parameter for numerous neurodegenerative diseases [ 115 ], which could increase neuroinflammation and over-stimulation of the endocannabinoid system [ 117 ]. AA bound to phospholipids determines the formation of eCB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), molecules involved in the regulation of neuroinflammatory responses by microglia and astrocytes [ 114 ].…”