Stoffel, Wilhelm, Schmidt-Soltau, Inga, Binczek, Erika, Thomas, Andreas, Thevis, Mario and Wegner, Ina (2020). Dietary omega 3-and omega 6-Polyunsaturated fatty acids reconstitute fertility of Juvenile and adult Fads2-Deficient mice. Mol. Metab., 36. AMSTERDAM: ELSEVIER. ISSN 2212-8778

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Objective: Polyunsaturated fatty acids (PUFAs), including essential fatty acids linoleic and a-linolenic acid and derived long chain and very long chain omega 3- and omega 6-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 Delta 6 fatty acid desaturase (FADS2) deficient mouse mutant lacking key enzyme activity in the biosynthesis of omega 3- and omega 6-PUFAs from FAs 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. Methods: Feeding regimens: Age-and gender-matched infertile fads2-/- mice were maintained on defined diets, normal diet containing essential fatty acids, and supplemented with omega 6-arachidonic acid, omega 3-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. Results: PUFA synthesis deficiency caused a halt to folliculogenesis, atresia of oocytes, and infertility of fads2-/- female mice. A PUFAdeficient 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. Conclusions: These findings demonstrate the previously unrecognized membrane structure-based molecular link between nutrient omega 3-and omega 6-PUFAs, gonadal membrane structures, and female and male fertility and might foster studies of the pivotal role of dietary PUFAs in human fertility. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (

Item Type: Journal Article
CreatorsEmailORCIDORCID Put Code
URN: urn:nbn:de:hbz:38-330898
DOI: 10.1016/j.molmet.2020.100974
Journal or Publication Title: Mol. Metab.
Volume: 36
Date: 2020
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2212-8778
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
Endocrinology & MetabolismMultiple languages


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