Background n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides.Methodology/Principal FindingsIn a ‘prevention study’, C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine.Conclusions/SignificanceCompared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.

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There is limited knowledge about the metabolism and function of n-3 very-long-chain polyunsaturated fatty acids (n-3 VLC-PUFAs) with chain lengths ≥24. They are known to be produced endogenously in certain tissues from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and not considered to originate directly from dietary sources. The aim of this study was to investigate whether n-3 VLC-PUFAs from dietary sources are bio-available and deposited in tissues of rat, fish and mouse. Rats were fed diets supplemented with a natural fish oil as source of low dietary levels of n-3 VLC-PUFAs, while Atlantic salmon and mice were fed higher dietary levels of n-3 VLC-PUFAs from a fish oil concentrate. In all experiments, n-3 VLC-PUFA incorporation in organs was investigated. We found that natural fish oil, due to its high EPA content, to a limited extent increased endogenous production of n-3 VLC-PUFAs in brain and eye of mice with neglectable amounts of n-3 VLC-PUFA originating from diet. When higher dietary levels were given in the form of concentrate, these fatty acids were bio-available and deposited in both phospholipids (PL) and triacylglycerol (TAG) fractions of all tissues studied, including skin, eye, brain, testis, liver and heart, and their distribution appeared to be tissue-dependent, but not species-specific. When dietary EPA and DHA were balanced and n-3 VLC-PUFA increased, the major n-3 VLC-PUFAs from the concentrate increased significantly in the organs studied, showing that these fatty acids can be provided through diet and thereby provide a tool for functional studies of these VLC-PUFAs.