Unravelling the systemic functions of omega3- and omega6-polyunsaturated fatty acids in genetically defined delta6-fatty acid desaturase (fads2-/-) deficient mouse mutants

• Applicant: Professor Dr. Wilhelm Stoffel
• Subject Area: Biochemistry ; Structural Biology ; Cell Biology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273917454

ω3- and ω6–polyenoic fatty acids (PUFAs) are essential structural elements of phospholipid classes in the lipid bilayer of all membranes of mammalian cells. They also function as precursors of pharmacologically highly active eicosa- and docosanoids. The role of ω3- and ω6–PUFAs in systemic homeostasis of lipid metabolism is in the focus of intensive research of many decades. The ratio of ω3-/ω6-PUFAs in western diet is regarded as essential epigenetic factor in the genetic regulation of lipid homeostasis. Imbalances of homeostasis are postulated as driving mechanism in the development of chronic metabolic diseases like hypertriglyceridemia and obesitas, fatty liver, type-2-diabetes, cardiovascular diseases, insulin resistance and inflammation and even neurodegenerative and psychiatric disease.Our present knowledge bases of numerous feeding experiments and epidemiological studies adresses the role of ω3- and ω6-PUFAs. Several of the disease syndroms, mentioned above, have been proposed as therapeutical targets for ω3-PUFAs altough our molecular understanding of their function is missing. The reasons of the ambiguity of results accumulated over decades is the complexity of the ω3- and ω6-PUFAs as substitutes in the phospholipidom of membranes and lipoprotein complexes, the heterogenity of the genetic background of animal models and patient collectives.So far no mammalian animal model was available to assess the role of ω3- and ω6-PUFAs in molecular studies of the systemic altered homeostasis. We have generated, by homologous recombination, a mouse model in which the key enzyme of the PUFA synthesis cascade, the Δ6 desaturase (FADS2), has been deleted. This mouse mutant is free of ω3- and ω6-PUFAs in extraneuronal tissue. Since the fads2-/- mouse is auxotrophic, it represents an ideal system to study it's pleitropic phenotype in unambiguous feeding experiments. We study in this genetically well definded mouse model in stringent feeding experiments the role of arachidonic acid, the main representative of the ω6-PUFA fatty acids, occuring in the "land food chain" and of docosahexanoic acid, the main representative of the ω3-PUFA fatty acids, occuring in the "sea food chain", as well as the role of the two essentiell fatty acids ω3-α-linolenic- (18:3) and ω6-linoleic-acid (18:2). Mechanistic and molecular studies elucidating the complexity of the pleiotropic phenotype in the fads2-/- mice can now be adressed in a limited number of genetically well defined and homogeneous experimental animals.

• DFG Programme: Research Grants