Obesity resistance and deregulation of lipogenesis in [Delta]6-fatty acid desaturase (FADS2) deficiency

• Published in: EMBO reports 2014-01, Vol.15 (1), p.110
• Main Authors: Stoffel, Wilhelm, Hammels, Ina, Jenke, Britta, Binczek, Erika, Schmidt-Soltau, Inga, Brodesser, Susanne, Odenthal, Margarete, Thevis, Mario
• Format: Article
• Language: English
• Subjects: Biosynthesis; Deregulation; Fatty acids; Homeostasis; Lipids; Membranes; Mutants; Obesity; Polyunsaturated fatty acids
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1002/embr.201338041

[Delta]-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 [omega]3- and [omega]6-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. [omega]6-Arachidonic (AA) and [omega]3-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. Synopsis Systemic absence of [omega]3- and [omega]6-polyunsaturated fatty acid (PUFA) in [Delta]6-fatty acid desaturase deficiency (fads2-/-) causes pleiotropy, of which obesity resistance and deregulation of lipogenesis are described here. In the fads2 null mutant, 18:2 is transformed to 20:35,11,14, which is incorporated as surrogate of PUFAs in the hydrophobic core of membrane phospholipid bilayers. This has a strong impact on membrane bound protein functions, e.g. SREBP1c maturation for regulated lipogenesis. Auxotrophy of the fads2-/- mutant allows the generation of the '[omega]6-arachidonic' and '[omega]3-docosahexaenoic fads2-/-' mouse lines, for studies of lipid homeostasis and PUFA related disease conditions. [PUBLICATION ABSTRACT]