With their findings Wilhelm Stoffel and his research team discovered a previously unrecognized membrane-structure-based molecular link between nutrient ω3-and ω6-PUFAs, gonadal membrane structures and female and male fertility. This data will be of great importance to further analyze the pivotal role of dietary PUFAs in human fertility.
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 critical factor in the pathogenesis of several human life style diseases: dyslipoproteinemia, obesity, cardiovascular and neurodegenerative diseases and infertility.
Infertility is a hall mark of the pleiotropic but auxotrophic fads2-/- phenotype, therefore congenial for stringent dietary studies on the role of individual PUFAs.
Wilhelm Stoffel comments: “The absence of unbiased animal models impedes molecular interpretation of the role of synthesized and dietary supplied PUFAs in these conditions. To overcome this, we used the Δ6-fatty acid desaturase (FADS2) deficient mouse mutant, lacking the 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.”
Using different 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 months old female and male fads2-/- mice.
Phospho- and sphingolipidomes of ovarian and testicular membrane lipid bilayers of each cohort were established and the impact on expression and topology of membrane marker proteins, membrane morphology, germ cell development and on female and male fertility in the respective cohorts elaborated.
PUFA-synthesis deficiency caused a halt of folliculogenesis, atresia of oocytes and infertility of fads2-/- female mice. PUFA-deficient membrane lipid-bilayer core structure led to the disassembly of the gap-junction network of the granulosa cell. In fads2-/- testis the blood-testis-barrier is 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 cycle, and the reconstitution of the blood-testis-barrier in Sertoli cells, reconstituting fertility not only in developing newborn, but surprisingly also in adult infertile fads2-/- female and male mice.
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.
Dietary ω3-and ω6-polyunsaturated fatty acids reconstitute fertility of juvenile and adult FADS2-deficient female and male mice
Wilhelm Stoffel, Inga Schmidt-Soltau, Erika Binczek, Andreas Thomas, Mario Thevis, Ina Wegner
Molecular Metabolism (available online March 17, 2020): https://doi.org/10.1016/j.molmet.2020.100974
Prof. Dr. Dr. Dr. Wilhelm Stoffel
CMMC Senior Research Group Leader at the CMMC
Laboratory of Molecular Neuroscience, Institute of Biochemistry, University of Cologne,
This project has been funded by the DFG (German Research Foundation). The DFG has continuously supported Professor Stoffel´s research ever since 1960, when returned as postdoc at the Rockefeller University, New York and the ETH Zürich, Switzerland.
Prof. Stoffel is now the oldest scientist funded by an individual research proposal of the DFG. He is head of the Senior Research Group at the Center of Molecular Medicine Cologne (CMMC) since his retirement in 1995. One focus of his research group is unraveling the molecular role of omega3- and omega6-polyunsaturated fatty acids in lipid metabolism and in the architecture and function of membrane systems of central nervous system, vascular and reproduction systems. For further information: https://www.cmmc-uni-koeln.de/events/workshops-and-conferences/symposium-molekuele-maeuse-und-menschen/cv-prof-wilhelm-stoffel
CMMC Central Office – Communication Debora Grosskopf-Kroiher