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Obesity resistance and deregulation of lipogenesis in Δ6‐fatty acid desaturase (FADS2) deficiency

Wilhelm Stoffel, Ina Hammels, Britta Jenke, Erika Binczek, Inga Schmidt‐Soltau, Susanne Brodesser, Margarete Odenthal, Mario Thevis

Author Affiliations

  1. Wilhelm Stoffel*,1,2,
  2. Ina Hammels1,2,
  3. Britta Jenke1,2,
  4. Erika Binczek1,
  5. Inga Schmidt‐Soltau1,
  6. Susanne Brodesser2,
  7. Margarete Odenthal3 and
  8. Mario Thevis4
  1. 1Center of Molecular Medicine (CMMC) Laboratory of Molecular Neurosciences, Institute of Biochemistry University of Cologne, Cologne, Germany
  2. 2Cluster of Excellence, Cellular Stress Response in Aging Related Diseases (CECAD), University of Cologne, Cologne, Germany
  3. 3Institute of Pathology, University of Cologne, Cologne, Germany
  4. 4Institute of Biochemistry, DHS Cologne, Cologne, Germany
  1. *Corresponding author. Tel: +49 221 478 6881; Fax: +49 221 478 6882; E‐mail: wilhelm.stoffel{at}uni-koeln.de
  1. WS designed and performed experiments, BJ, EB IH and ISS performed experiments, SB, MO and MT performed data analysis, WS and IH wrote the manuscript.

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.

Synopsis

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Systemic absence of ω3‐ and ω6‐polyunsaturated fatty acid (PUFA) in Δ6‐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 ‘ω6‐arachidonic’ and ‘ω3‐docosahexaenoic fads2/’ mouse lines, for studies of lipid homeostasis and PUFA related disease conditions.

Footnotes

  • The authors declare that they have no conflict of interest.

  • Received September 27, 2013.
  • Revision received October 21, 2013.
  • Accepted October 24, 2013.

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