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Obesity resistance and deregulation of lipogenesis in Δ6‐fatty acid desaturase ( FADS 2) deficiency
Author(s) -
Stoffel Wilhelm,
Hammels Ina,
Jenke Britta,
Binczek Erika,
SchmidtSoltau Inga,
Brodesser Susanne,
Odenthal Margarete,
Thevis Mario
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1002/embr.201338041
Subject(s) - lipogenesis , insulin resistance , stearoyl coa desaturase , obesity , fatty acid , medicine , endocrinology , biochemistry , biology , lipid metabolism , gene , gene expression
Δ‐6‐fatty acid desaturase ( FADS 2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids ( PUFA s), 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‐ PUFA s 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 PUFA s 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.