MOLMET
100974
100974
S2212-8778(20)30047-8
10.1016/j.molmet.2020.100974
The Author(s)
Original Article
Dietary ω3-and ω6-Polyunsaturated fatty acids reconstitute fertility of Juvenile and adult Fads2-Deficient mice
Wilhelm
Stoffel
1
2
3
∗
wilhelm.stoffel@uni-koeln.de
Inga
Schmidt-Soltau
2
Erika
Binczek
1
Andreas
Thomas
4
Mario
Thevis
4
Ina
Wegner
1
1
Laboratory of Molecular Neuroscience, Institute of Biochemistry, University of Cologne, 50931, Cologne, Germany
Laboratory of Molecular Neuroscience
Institute of Biochemistry
University of Cologne
Cologne
50931
Germany
Laboratory of Molecular Neuroscience, Institute of Biochemistry, University of Cologne, 50931, Cologne, Germany
2
CMMC (Center for Molecular Medicine), Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
CMMC (Center for Molecular Medicine)
Faculty of Medicine
University of Cologne
Cologne
50931
Germany
CMMC (Center for Molecular Medicine), Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
3
CECAD (Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases), University of Cologne, 50931, Cologne, Germany
CECAD (Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases)
University of Cologne
Cologne
50931
Germany
CECAD (Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases), University of Cologne, 50931, Cologne, Germany
4
Institute of Biochemistry, Deutsche Sporthochschule Cologne, 50933, Cologne, Germany
Institute of Biochemistry
Deutsche Sporthochschule Cologne
Cologne
50933
Germany
Institute of Biochemistry, Deutsche Sporthochschule Cologne, 50933, Cologne, Germany
∗
Corresponding author. Laboratory of Molecular Neuroscience, Institute of Biochemistry, University of Cologne, 50931, Cologne, Germany. fax: +49 221 478 6882.
Laboratory of Molecular Neuroscience
Institute of Biochemistry
University of Cologne
Cologne
50931
Germany
Abstract
Objective
Polyunsaturated 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.
Methods
Feeding 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.
Results
PUFA 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.
Conclusions
These 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.
Graphical abstract
Image 1
Highlights
•
PUFA-depletion disrupts membrane lipid scaffolds of ovarian GJ- and TJ-complexes of the testicular BTB
•
Nutrient AA/DHA reconstitute the gonadal membrane bilayer architecture in auxotrophioc fads2-/- mice
•
AA/DHA replenished lipid-bilayers promote the assembly of follicular GJ- and BTB-protein complexes in fads2-/- mice
•
Nutrient AA/DHA release arrest of oo- and spermatogenesis, restoring fertility of newborn and adult fads2-/- mice
Keywords
ω3-and ω6-PUFA deficiency
Auxotrophic fads2−/− mouse
Nutritional rescue of female and male fertility
Remodeling of membrane lipidomes
Reconstitution of junction systems of ovary and testis
KBJ00000000012864
2020-05-22T18:42:11
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S2212-8778(20)30047-8
10.1016/j.molmet.2020.100974
MOLMET
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2020-03-17T09:59:16Z
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