Neither Linoleic Acid nor Arachidonic Acid Promote White Adipose Tissue Inflammation in <i>Fads2−/−</i> Mice Fed Low Fat Diets

Dietary n‐6 polyunsaturated fatty acids (PUFAs) are widely perceived to promote inflammation and contribute to the development of cardiometabolic disease. However, emerging evidence casts doubt on the relationship between n‐6 PUFAs and inflammation, and suggests that different n‐6 PUFAs may influence this relationship differently. Establishing the roles of individual n‐6 PUFAs in vivo is challenging because linoleic acid (LA, 18:2n6) is endogenously and continuously converted into arachidonic acid (AA, 20:4n6). The fatty acid desaturase 2 gene ( Fads2 ) encodes the rate‐limiting delta‐6 desaturase enzyme necessary for converting LA into AA. The goal of this study was to elucidate the independent effects of the two predominant dietary n‐6 PUFAs, LA and AA, on inflammatory signalling in white adipose tissue (WAT) using Fads2 knockout ( Fads2 −/−) mice. We hypothesized that LA would not induce WAT inflammation unless it is converted into AA. Male C57BL/6 wild‐type (WT) and Fads2 −/− mice (n=8 per diet per genotype group) were fed low‐fat isocaloric diets containing either 7% corn oil w/w (containing ~42% LA) or 7% ARASCO oil w/w (containing ~27% AA) for 9 weeks. WAT gene expression, protein levels, and triacylglycerol (TAG) fatty acid composition were analyzed by qRT‐PCR, Western blots, and gas chromatography, respectively. Fads2 −/− mice fed the corn diet had no downstream AA, and reduced GLA (18:3n6) and DGLA (20:3n6), in TAGs compared to their WT counterparts. WT and Fads2 −/− mice fed the ARASCO diet had significantly higher levels of AA, DGLA, and GLA in TAGs compared to WT mice fed the corn diet. Estimated delta‐5 desaturase enzyme activity (AA: DGLA ratio) in WAT was reduced in Fads2 −/− mice fed the corn diet compared to their WT counterparts (p<0.05), and this was reflected by a 1.6‐fold reduction in FADS1 protein content (p<0.04). No differences in gene expression for common cytokines (e.g. Mcp‐1, Ccl5, Arg1, Nos2 ) and key regulators of oxylipin production (e.g. Cox‐2, Alox12, Alox15 ) were detected between WT and Fads2 −/− mice fed either diet. WT and Fads2 −/− mice fed both corn and ARASCO diets showed no difference in total or phosphorylated STAT3 and p38 proteins. These results suggest that in an unstimulated model neither LA nor AA promote WAT inflammation when consumed as part of a low‐fat diet. Support or Funding Information This work was supported by a grant from NSERC.

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