Circulating levels of endocannabinoids and oxylipins altered by dietary lipids in older women are likely associated with previously identified gene targets

• EC and oxylipin (OL) levels were altered by n − 3 PUFA in postmenopausal women (PMW).
• n − 3 treated PMW had changes in EC n − 6 ethanolamides and n − 3 diols/epoxides/alcohols.
• Phenotypic responses were observed with n − 3 PUFA supplementation in PMW.
• Increases in n − 3 acyl-ethanolamide/n − 3-derived OL support investigations on aging.
• These findings should be examined in genes associated with EC as previously found in mice.

Postmenopausal women (PMW) report marginal n − 3 PUFA intakes and are at risk of chronic diseases associated with the skeletal, muscular, neuroendocrine, and cardiovascular systems. How n − 3 PUFA affect the amounts of endocannabinoids (ECs) and oxylipins (OLs) of metabolic and physiologic importance in PMW is not clear. Based on our recent findings that dietary n − 3 PUFA alter gene targets of the EC system and lower pro-inflammatory OL we proceeded to characterize these actions in blood of PMW. Our aim was to determine levels of the ECs, OLs, and global metabolites (GM) in white PMW (75 ± 7 y), randomized in a double-masked manner, from baseline to 6 mo after receiving a fish oil supplement of n − 3 PUFA (720 mg 20:5n3 + 480 mg 22:6n3/d, n = 20) or placebo (1.8 g oleic acid/d, n = 20). ECs and OLs in serum were determined by UPLC-MS/MS and GM by GC–MS and LC-MS/MS. Plasma 20:5n3 and 22:6n3 levels increased in PMW given fish oil. EC n − 6 acyl-ethanolamides, arachidonate-derived diols were decreased and 20:5n3 and 22:6n3 diols, epoxides, and alcohols were increased in PMW given fish oil. GM analysis revealed that n − 3 PUFA supplementation increased renal steroid hormone and proteolytic metabolite levels in PMW. Herein, we confirm that gene targets of the EC system, previously found as modifiable by n − 3 PUFA result in changes in the levels of ECs and OLs in PMW. This study shows phenotypic responses (in levels) to n − 3 PUFA supplementation in PMW and increases of n − 3 acyl-ethanolamide and n − 3-derived OL of clinical considerations in aging.