Obesity resistance and deregulation of lipogenesis in Δ6‐fatty acid desaturase ( FADS 2) deficiency

Abstract

D-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 À/À mouse mutant to assess the enigmatic role of x3-and x6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2 À/À mutant, the molecular basis of which is unknown. Phospholipidomic profiling of membrane systems of fads2 À/À mice revealed diacylglycerol-structures, deprived of PUFAs but substituted with surrogate eicosa-5,11,14-trienoic acid. x6-Arachidonic (AA) and x3-docosahexaenoic acid (DHA) supplemented diets transformed fads2 À/À into AA-fads2 À/À and DHA-fads2 À/À mutants. Severely altered phospholipid-bilayer structures of subcellular membranes of fads2 À/À 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.

Polyunsaturated fatty acid regulation of adipocyte FADS1 and FADS2 expression and function

“…The current study validated the use of 3T3‐L1 adipocytes for studying diet regulation of the FADS enzymes and further showed that adipocyte FA content is influenced by the FADS pathway. Continuing this line of investigation is relevant given that the FADS enzymes are expressed in human adipose tissue and recent research in a Fads2‐/‐ mouse suggests a role for desaturases in the development of obesity‐related complications . Future investigations whereby desaturase expression is altered (i.e., over‐expressed or inhibited) in 3T3‐L1 cells will generate new insights regarding the role of these enzymes as mediators of PUFA content and bioactivity in adipocytes.…”

The Hypotriglyceridemic Effect of Sciadonic Acid is Mediated by the Inhibition of Δ9‐Desaturase Expression and Activity

“…Consequently, when cells lack a significant Δ6‐desaturase activity, such as K562, the synthesis of Scia is favored over its 20:3 isomer . Thus a fads2 −/− mouse mutant accumulates Scia in phospholipids by replacing, in part, arachidonic acid and other PUFA . The physiological effects of Scia were consequently attributed to this arachidonate substitution.…”

A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice

“…In such studies, D6D has received much more attention compared to D5D, with respect to metabolic disorders, because data demonstrated strong positive correlations between increased D6D activity and insulin resistance, BMI, and T2DM, while D5D activities showed negative correlation [15, 32–36]. Additionally, metabolic benefits of D6D inhibition were also predicted from the results that D6D KO mice exhibited resistance against HFD-induced obesity [37]. …”