Delta-6 Desaturase Inhibition Disrupts Lipid Storage and Metabolism in Murine White Adipose Tissue
Δ-6 Desaturase (D6D; encoded by the Fads2 gene) catalyzes the endogenous production of long-chain polyunsaturated fatty acids (LC-PUFA) from essential dietary fatty acids. Specifically, D6D initiates the biosynthesis of eicosanpentanoic acid (EPA) and docosahexaenoic acid (DHA) from a-linolenic acid (ALA). Recent evidence suggests that D6D inhibition not only disrupts LC-PUFA biosynthesis, but also reduces body weight and impacts whole-body lipid handling; however, the mechanisms remain largely unexplored. Therefore, the overall objective of this thesis was to investigate the effect of D6D inhibition on lipid storage and metabolism in white adipocytes by using the 3T3-L1 cell culture model and the Fads2 knockout (KO) mouse. We hypothesized that D6D inhibition would impair lipid storage and alter lipid metabolism in white adipocytes due to a disruption in EPA and DHA production. In the 3T3-L1 cell culture study, we found that D6D inhibition in differentiating adipocytes reduced triacylglycerol (TAG) accumulation and markers of fatty acid re-esterification in both ALA treated and non-treated conditions, indicating these effects are independent of a disrupted N-3 PUFA metabolism. In the Fads2 KO mouse study, male C57BL/6J Fads2 KO and wild-type (WT) mice were fed either a Lard diet (7% w/w lard) or a Flax diet (7% w/w flaxseed oil) for 21 weeks. Results showed that KO mice had reduced body weight, smaller white adipose tissue (WAT) depots, reduced adipocyte size, and a higher serum non-esterified fatty acid (NEFA) and NEFA/glycerol ratio compared to WT mice, regardless of the diet. In addition, lipogenic and lipolytic gene expression and protein abundance in WAT depots were higher in KO mice compared to WT mice. Genotype, but not diet, showed a significant main effect for most of the analyzed lipogenic and lipolytic markers in WAT depots. Moreover, the increase in markers of lipolysis in KO mice was accompanied by reduced insulin signaling in WAT depots. Collectively, the findings from this thesis suggests that D6D inhibition limits lipid storage by disrupting lipid metabolism and reducing insulin signaling in white adipocytes, which appear to be independent of disruptions in EPA and DHA synthesis due to D6D inhibition.