Abstract
α-Linolenic acid (ALA) is an essential fatty acid and the precursor for long-chain n-3 PUFA. However, biosynthesis of n-3 PUFA is limited in a Western diet likely due to an overabundance of n-6 PUFA. We hypothesized that dietary reduction of n-6/n-3 PUFA ratio is sufficient to promote the biosynthesis of long-chain n-3 PUFA, leading to an attenuation of high fat (HF) diet-induced obesity and inflammation. C57BL/6 J mice were fed a HF diet from ALA-enriched butter (n3Bu, n-6/n-3=1) in comparison with isocaloric HF diets from either conventional butter lacking both ALA and LA (Bu, n-6/n-3=6), or margarine containing a similar amount of ALA and abundant LA (Ma, n-6/n-3=6). Targeted lipidomic analyses revealed that n3Bu feeding promoted the bioconversion of long-chain n-3 PUFA and their oxygenated metabolites (oxylipins) derived from ALA and EPA. The n3Bu supplementation attenuated hepatic TG accumulation and adipose tissue inflammation, resulting in improved insulin sensitivity. Decreased inflammation by n3Bu feeding was attributed to the suppression of NF-κB activation and M1 macrophage polarization. Collectively, our work suggests that dietary reduction of the n-6/n-3 PUFA ratio, as well as total n-3 PUFA consumed, is a crucial determinant that facilitates n-3 PUFA biosynthesis and subsequent lipidomic modifications, thereby conferring metabolic benefits against obesity-induced inflammation and insulin resistance.
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Key Points
Numerous clinical and epidemiological studies have demonstrated that increased consumption of n-3 PUFA decreases the risks of a wide range of inflammatory diseases, including cardiovascular disease (CVD), non-alcoholic steatohepatitis, and insulin resistance. However, the typical American diet contains higher n-6 PUFA than n-3 PUFA, resulting in a significant imbalance between n-6/n-3 PUFA. Hence, there is an unmet need for a new dietary strategy that helps reduce n-6/n-3 PUFA ratio through daily regimen. Despite extensive studies on the role of ALA-rich oils in prevention from atherosclerosis, the understanding is limited as to whether the modulation of dietary n-6/n-3 ratio per se poses a direct impact on bioconversion for long-chain n-3 PUFA (i.e., DHA and EPA) and subsequent PUFA-derived oxygenated metabolites. In the current study, it was hypothesized that a dietary reduction of LA/ALA ratio could promote the biosynthesis of long-chain n-3 PUFA, thereby inducing metabolic benefits. The aim was to compare the differential impact of isocaloric high fat HF diet prepared from butter, ALA-enriched butter, and margarine on intracellular PUFA balance in obesity-prone C57BL/6 J mice. By taking a lipidomic approach, the study focused on investigating the impact of dietary n-6/n-3 PUFA ratio on endogenous production of long-chain n-3 PUFA and their oxygenated PUFA-metabolites as well as metabolic susceptibility to diet-induced inflammation. In this study, a margarine-based diet (Ma) did not exert metabolic benefits compared to a butter-based isocaloric diet (Bu), despite lower SFA and higher PUFA. In contrast, an ALA-enriched butter diet (n3Bu) reduced inflammatory responses and improved insulin sensitivity. Given that n3Bu contains a similar n-3 PUFA content with Ma, less total n-6 PUFA, and higher SFA than Ma, these results suggest that the n-6/n-3 PUFA ratio is a more critical metabolic determinant than the total dietary PUFA or SFA content.
The results further reinforce the idea that lowering dietary n-6/n-3 PUFA ratio by limiting dietary LA and enriching ALA in butter, is effective in boosting intracellular EPA production comparable to the degree of the genetic introduction of n-3 FA desaturase in Fat-1 mice. The findings demonstrated that reducing the n-6/n-3 PUFA ratio by enriching ALA in butter is effective in attenuating the HF diet-driven adiposity, inflammation, and insulin resistance in addition to the previous known cardio-protective effects. The study reinforces the notion that metabolic regulation relies on n-6/n-3 PUFA ratio rather than compositional changes in PUFA or SFA.