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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Endocannabinoids May Mediate the Ability of (n-3) Fatty Acids to Reduce Ectopic Fat and Inflammatory Mediators in Obese Zucker Rats^1–3,

⁴ Dipartimento Biologia Sperimentale, ⁵ Dipartimento di Scienze e Tecnologie Biomediche, and ⁶ Dipartimento di Neuroscienze, Università di Cagliari, Cagliari 09100, Italy; ⁷ Nutrisearch s.r.l. 09010 Pula, Italy; ⁸ CLANET Ltd., 02660 Espoo, Finland; ⁹ Aker Biomarine ASA, NO-0115 Oslo, Norway; and ¹⁰ Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy

Dietary (n-3) long-chain PUFA [(n-3) LCPUFA] ameliorate several metabolic risk factors for cardiovascular diseases, although the mechanisms of these beneficial effects are not fully understood. In this study, we compared the effects of dietary (n-3) LCPUFA, in the form of either fish oil (FO) or krill oil (KO) balanced for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content, with a control (C) diet containing no EPA and DHA and similar contents of oleic, linoleic, and -linolenic acids, on ectopic fat and inflammation in Zucker rats, a model of obesity and related metabolic dysfunction. Diets were fed for 4 wk. Given the emerging evidence for an association between elevated endocannabinoid concentrations and metabolic syndrome, we also measured tissue endocannabinoid concentrations. In (n-3) LCPUFA-supplemented rats, liver triglycerides and the peritoneal macrophage response to an inflammatory stimulus were significantly lower than in rats fed the control diet, and heart triglycerides were lower, but only in KO-fed rats. These effects were associated with a lower concentration of the endocannabinoids, anandamide and 2-arachidonoylglycerol, in the visceral adipose tissue and of anandamide in the liver and heart, which, in turn, was associated with lower levels of arachidonic acid in membrane phospholipids, but not with higher activity of endocannabinoid-degrading enzymes. Our data suggest that the beneficial effects of a diet enriched with (n-3) LCPUFA are the result of changes in membrane fatty acid composition. The reduction of substrates for inflammatory molecules and endocannabinoids may account for the dampened inflammatory response and the physiological reequilibration of body fat deposition in obese rats.

^* To whom correspondence should be addressed. E-mail: banni{at}unica.it or vdimarzo{at}icmib.na.cnr.it.

Manuscript received 19 January 2009. Initial review completed 28 January 2009. Revision accepted 30 May 2009.

Published online 23 June 2009.