title: Obesity resistance and deregulation of lipogenesis in Δ6-fatty acid desaturase (FADS2) deficiency.
abstract: Δ-6-fatty acid desaturase (FADS2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids (PUFAs), the essential structural determinants of mammalian membrane lipid-bilayers. We developed the auxotrophic fads2(-/-) mouse mutant to assess the enigmatic role of ω3- and ω6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2(-/-) mutant, the molecular basis of which is unknown. Phospholipidomic profiling of membrane systems of fads2(-/-)mice revealed diacylglycerol-structures, deprived of PUFAs but substituted with surrogate eicosa-5,11,14-trienoic acid. ω6-Arachidonic (AA) and ω3-docosahexaenoic acid (DHA) supplemented diets transformed fads2(-/-) into AA-fads2(-/-) and DHA-fads2(-/-) mutants. Severely altered phospholipid-bilayer structures of subcellular membranes of fads2(-/-) liver specifically interfered with maturation of transcription factor sterol-regulatory-element-binding protein, the key regulator of lipogenesis and lipid homeostasis. This study strengthens the concept that specific PUFA-substituted membrane phospholipid species are critical constituents of the structural platform operative in lipid homeostasis in normal and disease conditions.
authors.affiliation: Center of Molecular Medicine (CMMC) Laboratory of Molecular Neurosciences, Institute of Biochemistry University of Cologne, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stoffel
authors.forename: Ina
authors.initials: I
authors.lastname: Hammels
authors.forename: Britta
authors.initials: B
authors.lastname: Jenke
authors.forename: Erika
authors.initials: E
authors.lastname: Binczek
authors.forename: Inga
authors.initials: I
authors.lastname: Schmidt-Soltau
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Mario
authors.initials: M
authors.lastname: Thevis
mesh_terms: D052438:Adipocytes, White / Q000473:pathology; D052436:Adipose Tissue, White / Q000473:pathology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D048429:Cell Size; D060467:Disease Resistance; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology; D005260:Female; D019787:Linoleic Acid / Q000378:metabolism; D050602:Linoleoyl-CoA Desaturase / Q000172:deficiency* / Q000235:genetics; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D010743:Phospholipids / Q000378:metabolism; D059467:Transcriptome; D015430:Weight Gain
chemical_list: D010743:Phospholipids; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019787:Linoleic Acid; D050602:Linoleoyl-CoA Desaturase