Impact of dietary conjugated linoleic acid (CLA) on fatty acid metabolism and endocannabinoid biosynthesis

Background: Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid (LA) mainly found in the meat and dairy products of ruminants. CLA has been shown to possess different biological activities such as anticarcinogenic and anti-atherogenic properties, and also to influence body weight, energy and lipid metabolism, immune response, and inflammation. The endocannabinoid system (ECS) is involved in a variety of physiological processes, including the regulation of feeding behavior and energy homeostasis. ECS includes neuromodulatory archidonate-based lipids, the best characterized are 2-arachidonoyl-glycerol (2-AG) and N-arachidonoylethanolamine (AEA or anandamide), which activate specific cannabinoid receptors (CB1 and CB2). N-oleoylethanolamide (OEA) and Npalmitoylethanolamide (PEA) are generally termed as endocannabinoid-related compounds. OEA has been shown to decrease food intake and body weight gain, while PEA is known to possess anti-inflammatory activity. Conversely to endocannabinoids, OEA and PEA don’t exert their actions by activating cannabinoid receptors, but mostly through binding the peroxisome proliferator activated receptors (PPARs). Methodology: The aim of the present thesis was to evaluate the effects of dietary intake of CLA on fatty acid metabolism, tissue fatty acid incorporation and endocannabinoid biosynthesis in liver of obese Zucker rats and in plasma of healthy volunteers. 32 male rats were fed with an equimolar mix of c9,t11 and t10,c12 CLA isomers (about 1%) supplemented or not with two different background diets, one based on fat of vegetal origin, PO, and the other made with a fat content of animal origin, OF. Treatment lasted 3 months. In a randomized cross-over study we also evaluated the effects of very high doses of CLA on lipid profile and endocannabinoid levels in plasma of 24 healthy men and women (aged 18 to 65) who consumed each three distinct diets for three weeks. Diets were identical except for 7% of total energy (approximately 20 g/day) which was provided either by: CLA isomers (80% c9,t11 and 20% t10,c12), industrial trans fatty acids, or oleic acid (OA). Principal Findings: In Zucker rats, irrespective of the background diet CLA affected body and liver weight, with a reduced hepatic lipid deposition. CLA intake increased concentration of arachidonic acid (AA) with both PO or OF diets, and docosahexaenoic acid (DHA) only when CLA was included in the OF diet. CLA feeding in combination with PO diet only, increased retinol level. CLA intake resulted in a decrease of �9 desaturase index, which was inversely correlated to n-3 highly unsaturated fatty acid (HUFA) score in OF diet. In human plasma, CLA compared to OA diet decreased the metabolism and the incorporation of the LA metabolites, and influenced alpha linolenic acid (ALA) metabolism, which resulted in an increased n-3 HUFA score. Also, we confirmed as high doses of CLA reduced elongation of long chain fatty acids (LCFAs). CLA intake did not cause significant changes in the profile of endocannabinoids in liver of Zucker rats and in human plasma, but we found increased levels of PEA in OFCLA fed rats, and OEA in both OF and PO background diets supplemented with CLA. Conclusions: Based on our results, we conclude that the effects of CLA on fatty acid metabolism and endocannabinoid biosynthesis are strongly influenced by the background diet, which may also explain the differences found between experimental animals and humans. By improving n-6/n-3 HPUFA balance and sustaining PPAR� activity, directly and indirectly through OEA and PEA, CLA may exert its beneficial actions on human health and protection against some diseases, especially those characterized by chronic inflammation due to an impaired body fat deposition.