Abstract
Background – Omega-3 fatty acids, including DHA and α-linolenic acid (ALA), are proposed to improve metabolic health by reducing obesity-associated inflammation. Their effects are mediated in part by conversion to oxylipins. ALA is relatively understudied, and direct comparisons to other omega-3 fatty acids are limited. Objectives – We compared the effects of equal doses of ALA and DHA on plasma oxylipins and markers of metabolic health in women with obesity. Methods – We carried out a randomized, double-blind, crossover clinical trial where women aged 20–51 with a BMI of 30–51 kg/m2 were supplemented with 4 g/day of ALA or DHA for 4 weeks in the form of ALA-rich flaxseed oil or DHA-rich fish oil. The primary outcome, the plasma oxylipin profile, was assessed at Days 0 and 28 of each phase by HPLC-MS/MS. Plasma fatty acids, inflammatory markers, and the monocyte glucose metabolism were key secondary outcomes. Data were analyzed using a mixed model. Results – Compared to the baseline visit, there were higher plasma levels of nearly all oxylipins derived from DHA (3.8-fold overall; P < 0.001) and EPA (2.7-fold overall; P < 0.05) after 28 days of fish-oil supplementation, while there were no changes to oxylipins after flaxseed-oil supplementation. Neither supplement altered plasma cytokines; however, adiponectin was increased (1.1-fold; P < 0.05) at the end of the fish-oil phase. Compared to the baseline visit, 28 days of flaxseed-oil supplementation reduced ATP-linked oxygen consumption (0.75-fold; P < 0.05) and increased spare respiratory capacity (1.4-fold; P < 0.05) in monocytes, and countered the shift in oxygen consumption induced by LPS. Conclusions – Flaxseed oil and fish oil each had unique effects on metabolic parameters in women with obesity. The supplementation regimens were insufficient to reduce inflammatory markers but adequate to elicit increases in omega-3 oxylipins and adiponectin in response to fish oil and to alter monocyte bioenergetics in response to flaxseed oil.
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Key Points
Many of the biological effects of PUFAs have been attributed to the actions of their oxygenated free fatty acid metabolites, called oxylipins. Oxylipins are produced from precursor PUFAs by groups of intracellular enzymes in the cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP450) families. Dietary fatty acid intake influences the availability of precursor PUFAs for conversion to oxylipins; however, changes to oxylipin profiles do not necessarily reflect changes in the PUFA composition. Multiple chronic diseases are characterized by the presence of mitochondrial dysfunction in immune and other cells. The mitochondrial function is closely tied to the production of reactive oxygen species, which influences proinflammatory cytokine production and vice versa.
The authors report the results of a 2-phase, randomized, double blind, crossover clinical trial (NCT03583281) where females with abdominal obesity were supplemented with 4 g/day of ALA or DHA for 4 weeks in the form of ALA-rich flaxseed oil or DHA-rich fish oil (4:1 DHA/EPA). According to current disease models, abdominal obesity is harmful because adipocytes become hypertrophic and begin secreting chemokines and other factors.
Here, plasma adiponectin levels are slightly but significantly elevated after supplementation with DHA rich fish oil. Although the change in adiponectin occurred in the absence of reduced adiposity, defined by either body weight or BMI, it is possible that beneficial effects related to metabolic and/or cardiovascular functions might still occur. The most novel finding of this study is that monocyte OCR and ATP-linked OCR are reduced and spare respiratory capacity is increased after 4 weeks of flaxseed-oil supplementation. This suggests that these are beneficial effects, since a higher BMI is associated with a higher OCR and ATP-linked OCR but lower spare respiratory capacity. The study found that in parallel to a reduction in the resting OCR, flaxseed-oil supplementation also led to a dampened Warburg shift in response to 2 hours of LPS stimulation. In the presence of adequate glucose, the Warburg shift promotes a proinflammatory phenotype in innate immune cells. The combined
effect of a decreasing oxidative glucose metabolism at rest and diminishing the LPS-induced Warburg shift will reduce mitochondrial ROS production in monocytes and suppress a proinflammatory phenotype.
This study shows that ALA- and DHA-rich oils each have unique effects on plasma oxylipins and on markers of metabolic health in women with obesity. Four-week supplementation with 4 g/day of ALA was insufficient to alter oxylipin, blood lipid, or inflammatory profiles in the study population; however, the monocyte bioenergetic profiles were markedly changed. These disparate effects provide further evidence that omega-3 PUFAs are not interchangeable and may provide metabolic benefits by entirely different, and possibly complementary, mechanisms.