Abstract
Fatty acid desaturase 2 (Fads2) encodes the delta-6 desaturase (D6D) enzyme, which is rate-limiting for the endogenous production of omega-3 long-chain polyunsaturated fatty acids (LC-PUFA). Numerous studies have reported the cardiometabolic health benefits of omega-3 LC-PUFA. Humans carrying genetic variants in the FADS2 gene have reduced levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as their derived oxylipins, in blood, erythrocytes and white adipose tissue (WAT). Similar findings have been reported in whole-body Fads2−/− mice fed a diet deficient in omega-3 LC-PUFA. The objective of this study was to determine if a diet containing EPA and DHA would prevent the deficiencies in WAT lipid profiles seen in Fads2−/− mice fed a diet containing only ALA. Male C57BL/6 J Fads2−/− and wild type (WT) mice were fed a low fat (7% w/w) diet for 9 weeks containing either flaxseed oil + ARASCO (FD, containing~53% ALA) or menhaden oil (MD, containing~14% EPA and 10% DHA). Fads2−/− mice fed an ALA-enriched diet had reduced body weight, little-to-no omega-3 LC-PUFA and a near complete loss of all omega-3 derived oxylipins in both epididymal and inguinal WAT (P<.05) compared to their WT counterparts, as well as altered expression of key regulators of the fatty acid desaturase pathway. However, Fads2−/− mice fed a diet containing EPA and DHA prevented most of these changes. This study provides evidence that a diet containing EPA and DHA provides a nutritional strategy to prevent alterations in WAT lipid content caused by reduced D6D activity.
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Key Findings
Mammalian cells can convert ALA and linoleic (LA) into eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6), respectively. The pathway regulating the conversion of essential FA into EPA, DHA, and AA is regulated by the delta-6 desaturase (D6D), which is encoded by the fatty acid desaturase 2 (Fads2) gene. Recent work has shown that polymorphisms in the human FADS2 gene influence FA profiles in white adipose tissue (WAT) depots with carriers of risk alleles showing reduced D6D activity and, consequently, lower levels of LC-PUFA. The goal of this study was to examine how different omega-3 diets shape FA and oxylipin (eicosanoid substances) content in two different WAT depots in the context of reduced D6D activity. Key regulators of FADS pathway activity, FA composition, and oxylipin profiles in both subcutaneous and visceral WAT in wild-type and Fads2-/- mice fed a diet supplemented with either flaxseed oil (ALA) or menhaden oil (EPA and DHA) were examined. It was postulated that when ALA is the only omega-3 present in the diet, Fads2-/- mice would experience altered expression in FADS pathway regulators, as well as changes in FA and oxylipin content in WAT depots. It was also hypothesized that feeding Fads2-/- mice a diet rich in EPA and DHA would prevent any changes caused by reduced D6D activity.
The present study demonstrated that when D6D activity is reduced, the consumption of a diet containing EPA and DHA provides a nutritional approach to ensure that omega-3 LC-PUFA and oxylipin content are conserved in WAT. The novel and key findings from this study include: i) consumption of EPA and DHA prevents the reduction in body weight observed in Fads2-/- mice fed an ALA-enriched diet, ii) Fads2-/- mice fed a diet that contains only ALA have little-to-no omega-3 LC-PUFA or derived oxylipins in either WAT depot, and iii) consumption of EPA and DHA prevents the aforementioned changes in WAT lipid content in Fads2-/- mice. With the exception of changes in Fads1 and Elovl2 gene expression and ELOVL2 protein in eWAT of Fads2-/- mice, our study found little difference between the two WAT depots. Together, this work suggests that providing dietary EPA and DHA in the context of reduced D6D activity warrants investigation as a nutritional approach to prevent deficiencies in WAT lipid and oxylipin content. In the current study, the two WAT depots responded differently to Fads2 deficiency at the level of both omega-3 LC-PUFA composition and gene expression. Fads2-/- FD mice lacked DPA and DHA in both TG and PL fractions in both depots, and lacked EPA in TAGs but not PLs. Oxylipins are important pro- and anti-inflammatory mediators produced from omega-3 and omega-6 LC-PUFA, and play integral roles in maintaining healthy, functional WAT. The majority of omega-3 LC-PUFA derived oxylipins were completely absent in Fads2-/- FD mice compared to WT FD mice. However, feeding Fads2-/- mice a diet containing EPA and DHA prevented these changes in oxylipin content. The changes in omega-3 LC-PUFA and all associated oxylipins observed in Fads2-/- mice fed an ALA-supplemented diet were prevented when feeding knock-out mice a diet containing EPA and DHA. The consumption of ALA in the context of a functional D6D enzyme is able to establish WAT omega-3 LC-PUFA and oxylipin content, but not to the same extent as consuming EPA and DHA directly. This suggests that deficiencies in omega-3 LC-PUFA and oxylipin content associated with reduced D6D activity (i.e, in individuals carrying variants in the FADS1/FADS2 gene cluster) could be circumvented with a diet containing EPA and DHA.