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Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ?3- and ?6-long-chain-PUFA deficiency.

ABSTRACT: 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.

SUBMITTER: Hammels I

PROVIDER: S-EPMC6672042 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Hammels Ina I Binczek Erika E Schmidt-Soltau Inga I Jenke Britta B Thomas Andreas A Vogel Matthias M Thevis Mario M Filipova Dilyana D Papadopoulos Symeon S Stoffel Wilhelm W

Journal of lipid research 20190605 8

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<sub>i/o</sub> 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 c ...[more]

PMID: 31167809

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Project description:ObjectivePolyunsaturated fatty acids (PUFAs), including essential fatty acids linoleic and α-linolenic acid and derived long chain and very long chain ω3-and ω6-polyunsaturated fatty acids, are vital structures in mammalian membrane systems and signaling molecules, pivotal in brain development, lipid, and energy metabolism and in female and male fertility during human evolution. Numerous nutritional studies suggest imbalance of PUFA metabolism as a critical factor in the pathogenesis of several human lifestyle diseases: dyslipoproteinemia, obesity, cardiovascular and neurodegenerative diseases, and infertility. The lack of unbiased animal models impedes molecular interpretation of the role of synthesized and dietary supplied PUFAs in these conditions. In this study, we used a Δ6 fatty acid desaturase (FADS2) deficient mouse mutant lacking key enzyme activity in the biosynthesis of ω3-and ω6-PUFAs from EFAs to address the molecular role of PUFAs in female and male fertility. Infertility is a hallmark of the pleiotropic but auxotrophic fads2-/- phenotype and is therefore helpful for stringent dietary studies on the role of individual PUFAs.MethodsFeeding regimens: Age- and gender-matched infertile fads2-/- mice were maintained on defined diets, normal diet containing essential fatty acids, and supplemented with ω6-arachidonic acid, ω3-docosahexaenoic acid, and arachidonic/docosahexaenoic acid, starting (a) after weaning and (b) initiated in 4-month-old female and male fads2-/- mice. Phospho- and sphingolipidomes of ovarian and testicular membrane lipid bilayers in each cohort were established and the impact on the expression and topology of membrane marker proteins, membrane morphology, germ cell development, and female and male fertility in the respective cohorts was elaborated.ResultsPUFA synthesis deficiency caused a halt to folliculogenesis, atresia of oocytes, and infertility of fads2-/- female mice. A PUFA-deficient membrane lipid bilayer core structure led to the disassembly of the gap junction network of the follicular granulosa cells. In fads2-/- testis, the blood-testis barrier was disrupted and spermatogenesis arrested, leading to infertility. Sustained supply of combined AA and DHA remodeled the PUFA-deficient ovarian and testicular membrane lipidomes, facilitating the reassembly of the functional gap junction network for regular ovarian cycles and the reconstitution of the blood-testis barrier in Sertoli cells, reconstituting fertility not only in developing newborns, but surprisingly also in adult infertile fads2-/- mice.ConclusionsThese findings demonstrate the previously unrecognized membrane structure-based molecular link between nutrient ω3-and ω6-PUFAs, gonadal membrane structures, and female and male fertility and might foster studies of the pivotal role of dietary PUFAs in human fertility.

Project description:Arachidonic acid (ARA, 20:4n-6) and dihomo-γ-linolenic acid (DGLA, 20:3n-6) are omega-6 long-chain polyunsaturated fatty acids (LC-PUFA), which are key precursors for lipid mediators of the immune system and inflammatory response. The microalga Lobosphaera incisa (WT) and its Δ5-desaturase mutant P127 (MUT) are unique photosynthetic sources for ARA and DGLA, respectively. This study explores the effect of dietary supplementation with L. incisa and P127 biomass on tissue fatty acid composition, immune function, and disease resistance in zebrafish (Danio rerio). The broken microalgal biomass was added to commercial fish feed at 7.5 and 15% (w/w), providing 21.8 mg/g feed ARA for the WT-supplemented group and 13.6 mg/g feed DGLA for the MUT-supplemented group at the 15% inclusion levels. An unsupplemented group was used as the control. After 1 month of feeding, fish were challenged with Streptococcus iniae. Fish were sampled before the challenge and 1 week after the challenge for various analyses. Tissue ARA and DGLA levels significantly increased in the liver, corresponding to microalgal supplementation levels. The elevated expression of specific immune-related genes was evident in the kidneys in all treatment groups after 1 month of feeding, including genes related to eicosanoid synthesis, lysozyme, and NF-κB. In the liver, microalgal supplementation led to the upregulation of genes related to immune function and antioxidant defense while the expression of examined genes involved in ARA metabolism was downregulated. Importantly, fish fed with 15% of both WT- and MUT-supplemented feed showed significantly (p < 0.05) higher survival percentages (78 and 68%, respectively, as compared to only 46% in the control group). The elevated expression of genes related to inflammatory and immune responses was evident post-challenge. Collectively, the results of the current study demonstrate the potential of microalgae-derived dietary ARA and DGLA in improving immune competence and resistance to bacterial infection in zebrafish as a model organism.

Project description:The interaction of dietary eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) levels with omega-6 to omega-3 ratios (ω6:ω3), and their impact on head kidney lipid metabolism in farmed fish, are not fully elucidated. We investigated the influence of five plant-based diets (12-week exposure) with varying EPA+DHA levels (0.3, 1.0, or 1.4%) and ω6:ω3 (high ω6, high ω3, or balanced) on tissue lipid composition, and transcript expression of genes involved in fatty acid and eicosanoid metabolism in Atlantic salmon head kidney. Tissue fatty acid composition was reflective of the diet with respect to C18 PUFA and MUFA levels (% of total FA), and ω6:ω3 (0.5-1.5). Fish fed 0.3% EPA+DHA with high ω6 (0.3% EPA+DHA↑ω6) had the highest increase in proportions (1.7-2.3-fold) and in concentrations (1.4-1.8-fold) of arachidonic acid (ARA). EPA showed the greatest decrease in proportion and in concentration (by ~½) in the 0.3% EPA+DHA↑ω6 fed fish compared to the other treatments. However, no differences were observed in EPA proportions among salmon fed the high ω3 (0.3 and 1.0% EPA+DHA) and balanced (1.4% EPA+DHA) diets, and DHA proportions were similar among all treatments. Further, the transcript expression of elovl5a was lowest in the 0.3% EPA+DHA↑ω6 fed fish, and correlated positively with 20:3ω3, 20:4ω3 and EPA:ARA in the head kidney. This indicates that high dietary 18:3ω3 promoted the synthesis of ω3 LC-PUFA. Dietary EPA+DHA levels had a positive impact on elovl5a, fadsd5 and srebp1 expression, and these transcripts positively correlated with tissue ΣMUFA. This supported the hypothesis that LC-PUFA synthesis is positively influenced by tissue MUFA levels in Atlantic salmon. The expression of pparaa was higher in the 0.3% EPA+DHA↑ω6 compared to the 0.3% EPA+DHA↑ω3 fed fish. Finally, significant correlations between head kidney fatty acid composition and the expression of eicosanoid synthesis-related transcripts (i.e., 5loxa, 5loxb, cox1, cox2, ptges2, ptges3, and pgds) illustrated the constitutive relationships among fatty acids and eicosanoid metabolism in salmon.

Dataset Information

Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ?3- and ?6-long-chain-PUFA deficiency.

Publications

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

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