Oils Rich in α-Linolenic Acid or Docosahexaenoic Acid Have Distinct Effects on Plasma Oxylipin and Adiponectin Concentrations and on Monocyte Bioenergetics in Women with Obesity

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. This trial was registered at clinicaltrials.gov as NCT03583281.

Keywords: adiponectin; bioenergetics; docosahexaenoic acid; inflammation; metabolism; obesity; omega-3 fatty acids; oxylipins; α-linolenic acid.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

CONSORT chart of study subjects. After contacting 86 individuals and screening 40, 8 individuals did not meet the inclusion criteria. Of 32 eligible individuals, 30 were randomized, while 2 declined to participate. The completion rate varied between phases due to the randomized crossover nature of the study. The analysis of the fish oil arm of the study was based on 22 individuals, and the analysis of flaxseed oil was based on 21 individuals. ALA, α-linolenic acid.

FIGURE 2

Effects of flaxseed-oil and fish-oil supplementation on plasma ALA, EPA, and DHA oxylipins and their fatty acid precursors in women with obesity. (A) Selected plasma oxylipins (n = 21) and (B) total plasma fatty acids (n = 21–22) are shown for day 0 and day 28 of each phase. Data were analyzed using a mixed model, and pairwise comparisons were assessed by difference of least square means with adjusted P values (Tukey-Kramer correction). *P < 0.05, **P <  0.01, and ***P < 0.001. Complete statistical analyses are provided in Table 3 and Supplemental Table 4 for all oxylipins and in Table 2 and Supplemental Table 5 for all fatty acids. ALA, α-linolenic acid.

FIGURE 3

Flaxseed-oil supplementation alters the monocyte glucose metabolism in women with obesity. Bioenergetics parameters of CD14+CD16– monocytes purified from peripheral blood on day 0 and 28 of each phase were assessed using a Seahorse XF mitochondrial stress test in the presence of glucose. (A) Correlations between BMI and parameters at the first study visit (n = 15). Pearson coefficients (r) and P values are indicated. (B) Supplementation effects on selected bioenergetics parameters (n = 12–15). Data were analyzed using a mixed model, and pairwise comparisons were assessed by difference of least square means with adjusted P values (Tukey-Kramer correction). *P < 0.05. Complete statistical analyses of all bioenergetics parameters are in Table 6 and Supplemental Table 8. (C) Visualization of cell energy phenotypes of unstimulated and 2-hour LPS-stimulated cells. OCR and ECAR measurements represent mean values from 10–15 participants. ECAR, extracellular acidification rate; OCR, oxygen consumption rate; SRC, spare respiratory capacity.