Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids

Martin Rossmeisl,Gudmundur G Haraldsson,Iren Stoknes,Kitty C M Verhoeckx,Eva Tvrzicka,Barbora Stankova,Dasa Medrikova,Michiel G J Balvers,Ondrej Kuda,Morten Bryhn,Jan Kopecky,Tomas Jelenik,Zuzana Macek Jilkova,Harald Svensen,Peter Sjövall,Ylva Magnusson,Björn Kristinsson

doi:10.1371/journal.pone.0038834

Abstract

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.

Highlights

Obesity and associated diseases such as type 2 diabetes, dyslipidemia and hypertension, i.e. components of the metabolic syndrome [1], are a major public health problem
The results suggest that dietary docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in the form of marine fish phospholipids are superior to triglycerides with respect to the preservation of glucose homeostasis and the reversal of hepatic steatosis, adipocyte hypertrophy and low-grade white adipose tissue (WAT) inflammation
Prevention of Obesity-associated Disorders To characterise the efficacy of LC n-3 PUFA in the prevention of adverse consequences of high-fat intake (Fig. 1), three-monthold mice were fed for a 9-week-period either on a corn oil-based high-fat diet or treated by isocaloric corn oil-based high-fat obesogenic diet (cHF)-based diets with DHA and EPA (DHA/EPA) supplemented as triglycerides (30 g DHA/EPA per kg diet; cHF+v3TG diet) or phospholipids (10 or 30 g DHA/EPA per kg diet; cHF+v3PL diet; Table S1, S2)

Summary

Introduction

Obesity and associated diseases such as type 2 diabetes, dyslipidemia and hypertension, i.e. components of the metabolic syndrome [1], are a major public health problem. While effective pharmacological interventions for the treatment of obesityassociated diseases require the use of multiple agents and are often associated with adverse side-effects, lifestyle modifications remain an essential component of treatment strategies In this respect, dietary intake of marine fish oils, namely long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) such as docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3), have been shown to exert profound hypolipidemic effects [2,3], reducing systemic inflammation [4,5] as well as low-grade inflammation of white adipose tissue (WAT; [6,7,8,9]) and limiting hepatosteatosis [8,9,10,11,12], resulting in a decrease in cardiovascular morbidity and the incidence of type 2 diabetes in humans [13,14]. The inhibition of the endocannabinoid system activity leads to beneficial metabolic effects, reflecting multiple mechanisms of endocannabinoid action mediated by their specific receptors as well as by PPAR-a (reviewed in [23,27])

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Conclusion