Novel CB1-ligands maintain homeostasis of the endocannabinoid system in {omega}3- and {omega}6-long-chain-PUFA deficiency [Research Articles]

Mammalian 3- and 6-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 Gi/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 6-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, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded 8-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.

Source: The Journal of Lipid Research - July 31, 2019 Category: Lipidology Authors: Hammels, I., Binczek, E., Schmidt-Soltau, I., Jenke, B., Thomas, A., Vogel, M., Thevis, M., Filipova, D., Papadopoulos, S., Stoffel, W. Tags: Research Articles Source Type: research