TY - JOUR
T1 - Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency
AU - Hammels, Ina
AU - Binczek, Erika
AU - Schmidt-Soltau, Inga
AU - Jenke, Britta
AU - Thomas, Andreas
AU - Vogel, Matthias
AU - Thevis, Mario
AU - Filipova, Dilyana
AU - Papadopoulos, Symeon
AU - Stoffel, Wilhelm
N1 - Copyright © 2019 Hammels et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2019/8
Y1 - 2019/8
N2 - 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 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 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, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded 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.
AB - 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 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 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, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded 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.
U2 - 10.1194/jlr.M094664
DO - 10.1194/jlr.M094664
M3 - Journal articles
C2 - 31167809
SN - 0022-2275
VL - 60
SP - 1396
EP - 1409
JO - Journal of lipid research
JF - Journal of lipid research
IS - 8
ER -