Oils rich in alpha-linolenic acid and docosahexaenoic acid have distinct effects on lipid mediators, adiponectin levels and monocyte bioenergetics in women with obesity Samantha D. Pauls1,2, Lisa R. Rodway2,3, Harold M. Aukema1,2, Peter Zahradka1,2,3, Carla G. Taylor1,2,3 1Department of Food and Human Nutritional Sciences, University of Manitoba, Canada 2Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada 3Department of Physiology and Pathophysiology, University of Manitoba, Canada Background: Omega-3 fatty acids such as fish oil-derived docosahexaenoic acid (DHA) and plant oil-derived alpha-linolenic acid (ALA) have been proposed to improve metabolic health by reducing obesity-associated inflammation. Their effects are thought to be mediated in part by their conversion to oxygenated free fatty acid metabolites, called oxylipins. ALA has so far been relatively understudied and only a few investigations have directly compared its potency with other omega-3 fatty acids in humans. Methods: Here, we report the results of a randomized, double-blind crossover clinical trial where females with abdominal obesity were supplemented with 4 g/day ALA or DHA for 28 days in the form of ALA-rich flaxseed oil or DHA-rich fish oil. The primary outcome was the plasma oxylipin profile, assessed by high performance liquid chromatography tandem mass spectrometry. Secondary outcomes included plasma fatty acids measured by gas chromatography, plasma cytokines and adipokines measured by electrochemiluminescence (Meso Scale Discovery), and monocyte bioenergetics measured by mitochondrial stress test (Seahorse XF). Results: DHA supplementation increased plasma levels of DHA and eicosapentaenoic acid (EPA), as well as their oxylipin metabolites, and decreased plasma levels of several saturated, monounsaturated, and omega-6 fatty acids. ALA supplementation increased ALA itself and eicosatrienoic acid but had no effect on other fatty acids or on oxylipins. Neither supplement altered plasma pro-inflammatory markers (IFN-g, IL-1b, IL-6, IL-8, IL-17A, TNF-a, VEGF), an anti-inflammatory marker (IL-10) or resistin. However, DHA but not ALA increased plasma levels of adiponectin, an insulin-sensitizing adipokine. At first study visit, higher BMI was associated with higher ex vivo oxygen consumption rate (OCR) in purified monocytes. ALA reduced basal- and ATP-linked OCR while DHA had no effect on bioenergetics. Conclusions: ALA and DHA each had unique effects on metabolic parameters in females with obesity. Confirming previous studies, we found that DHA improves adipocyte function in vivo as evidenced by increased plasma adiponectin. We also report, for the first time, that ALA supplementation counters the increase in monocyte oxidative glucose metabolism observed with higher BMI. DHA substantially altered plasma fatty acid and oxylipin profiles while ALA had minimal impact. Thus, ALA and DHA differ considerably in their biological effects and in the mechanisms by which they carry out these effects in women with obesity. Funding source: The Canadian Institutes of Health Research.