Abstract
Introduction: Consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been reported to provide health benefits, but it remains unknown whether the fatty acids themselves or their oxygenated metabolites, oxylipins, are responsible for the beneficial effects. Purpose: This paper describes the design and rationale of a randomized, double-blinded, cross-over study comparing the effects of α-linolenic acid (ALA)-rich flax oil and docosahexaenoic acid (DHA)-rich fish oil supplementation on circulating oxylipin profiles in females with obesity, in relation to obesity-induced inflammation. Methods and analysis: Pre-menopausal females (n = 24) aged 20-55 with a BMI ≥30, will consume capsules containing flaxseed oil (4 g ALA/day) or fish oil (4 g DHA + 0.8 g EPA/day) during 4-week supplementation phases, with a minimum 4-week washout. The primary outcome is alterations in plasma oxylipin profiles. Secondary outcomes include effects of supplementation on circulating markers of inflammation, adipokines, plasma fatty acid composition, blood lipid profile, anthropometrics, oxylipin and cytokine profiles of stimulated immune cells, monocyte glucose metabolism, blood pressure and pulse wave velocity. Ethics and significance: This trial has been approved by the University of Manitoba Biomedical Research Ethics Board and the St. Boniface Hospital Research Review Committee. The study will provide information regarding the effects of ALA and DHA supplementation on oxylipin profiles in obese but otherwise healthy females. Additionally, it will improve our understanding of the response of circulating inflammatory mediators originating from immune cells, adipose tissue and the liver to n-3 PUFA supplementation in relation to the metabolic features of obesity.
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Key Points
The oxylipin profile is thought to be pathologically altered in obesity. Examination of how oxylipin profiles are altered in obesity may explain their beneficial and detrimental effects and allow targeted therapies and interventions to be developed. N-3 PUFAs have emerged as potential therapeutic agents, however, their effects on oxylipin profiles in the context of obesity have not been thoroughly examined. A direct comparison of DHA and ALA supplementation in the context of obesity with respect to their effects on plasma oxylipin profiles, obesity-associated inflammation and other clinical parameters is needed to address these questions. This study, the Effects of Dietary Fatty Acids on Octadecanoid Production and Biological Actions in Obesity-Induced Inflammation (OXBIO) trial was designed as a randomized, double-blind, cross-over intervention trial to compare the effects of supplementation with ALA-rich flax oil and DHA-rich fish oil for four weeks on the plasma oxylipin profile and inflammation- and obesity-associated parameters of pre-menopausal cis-gendered females with obesity.
Assessments before and after supplementation will include plasma oxylipin profile, fatty acid composition, adipokines (adiponectin, resistin), markers of inflammation (interleukin-6 [IL-6], IL-1β, IL-8, IL-17A interferon-γ [INF-y], IL-10, tumor necrosis factor-α [TNF-α], vascular endothelial growth factor [VEGF], C-reactive protein [CRP]), and markers of metabolic function. In addition, the oxylipin profile and cytokines (INF-y, IL-1β, IL-6, IL-8, IL-10, TNF-α) produced by peripheral blood mononuclear cells (PBMC) in response to stimulation (TLR4, TLR7/8 ligands) and in relation to PBMC fatty acid composition will be investigated along with monocyte glucose metabolism and PBMC gene expression. This study design will provide new information on oxylipin profile changes in response to n-3 PUFA supplementation in a population of obese women without chronic illness and enable one of the first comparisons of ALA-and DHA-responsive oxylipins within the context of obesity. It will also inform understanding of relationships among indices of inflammation originating from adipose tissue (adipokines), liver (CRP) and immune cells (cytokines), with the plasma oxylipin profile and the metabolic health of the participants, in response to n-3 PUFA supplementation.
The OXBIO study aims to compare the effects of short-term plant-based versus marine-based n-3 PUFA supplementation on oxylipin profiles and their relationship to clinically important metabolic parameters in females with obesity. Specifically it will explore how these dietary fatty acids alter the plasma oxylipin profile and influence features of obesity-induced inflammation. Using the study design described here, supplementation with equal doses of ALA and DHA will be compared over 4 weeks in cis-gendered females with obesity. This study is unique as the impact on oxylipin profiles and inflammatory markers in plasma and secreted from stimulated immune cells will be examined side-by-side. It is predicted that ALA and DHA supplementation will uniquely alter the oxylipin profile and that oxylipin profiles will be different in participants with varying degrees of obesity. The oxylipin profile as well as inflammatory marker production are thought to be pathologically altered in obesity. We hypothesize that fatty acid supplementation with ALA or DHA may beneficially alter the oxylipin profile as well as inflammatory markers associated with obesity. Furthermore, certain oxylipins are predicted to be correlated with a reduction in inflammation and will be produced at higher levels in responders versus non-responders, as measured by reductions in key cytokines, such as IL-6, TNF-α, and CRP.
It is expected that alterations in oxylipin and cytokine profiles would precede such changes and may serve as important biomarkers. The results obtained may inform future studies examining functional outcomes in longer-term trials. This study may explain how changes in oxylipin levels influence the pathogenesis of obesity-induced inflammation in pre-menopausal females. Furthermore, examining the oxylipins and cytokines produced by immune cells challenged with pattern recognition receptor ligands, and the bioenergetic profiles of monocytes, will further contribute to our understanding of how ALA and DHA supplementation influence immune cell responsiveness. Taken together, this information will provide the basis for future studies elucidating the biological roles of these fatty acid metabolites. This may then assist in the development of more targeted strategies to treat and prevent obesity and its associated comorbidities.