EFFECTS OF N-OLEOYLETHANOLAMINE AND THE PPARα AGONIST FENOFIBRATE ON FEEDING, ACTIVITY AND METABOLIC RATE IN MICE

Annie Patel, Preeti Jethwa, Sarir Sarmad, David. A. Kendall, Stephen. P. H. Alexander, Francis. J. P. Ebling
University of Nottingham, Nottingham, United Kingdom

OEA (N-oleoylethanolamine) is an endogenous compound which has been proposed to be a peripheral satiety signal, since it increases in the small intestine after feeding (Fu et al., 2003) and reduces food intake and body weight gain in mice (Rodriguez de Fonseca et al., 2001), possibly through peroxisome proliferator-activated receptor alpha (PPARα) present in the small intestine (Guzman et al., 2004). The aim of this investigation was to compare the actions of OEA and the PPARα agonist fenofibrate on food intake and energy expenditure. Eight adult male C57bl mice received a single intraperitoneal injection of either vehicle (5% Tween 80, 5% polyethylene glycol, 90% sterile saline), OEA (10 mg kg-1), fenofibrate (20 mg kg-1) or both OEA/fenofibrate (10 mg kg-1 and 20 mg kg-1, respectively). Treatments were given in a pseudo-random order in rotation over four weeks so each animal acted as its own control. Metabolic parameters were measured over 24 hours using the Columbus Instruments OxyMax indirect calorimeter system.

OEA elicited a transient decrease in food intake (vehicle 0.19 ± 0.02, OEA 0.075 ± 0.02; P<0.05, 1-way ANOVA with Dunnett’s multiple comparison test) 0-2 hours post-injection, whereas fenofibrate only produced a marginal reduction (0.10 ± 0.04 g). In the presence of fenofibrate, there was no change in the response to OEA over the same period (0.06 ± 0.03 g, P<0.01). Whereas the inhibitory effect of OEA was lost after 2 hours, co-administration of OEA and fenofibrate continued to suppress food intake for 24 hours post-injection (vehicle 6.94 ± 1.07; test 4.02 ± 0.46 g; P<0.01). Administration of OEA (1369 ± 108 ml kg-1 hr-1; P<0.05) and OEA/fenofibrate (1277 ± 143; P<0.01), but not fenofibrate alone (1625 ± 76), elicited a reduction in oxygen consumption at 30 min compared to vehicle (1682 ± 133). Within the first hour, OEA (271 ± 32 activity counts min-1; P<0.01) and OEA/fenofibrate (234 ± 29; P<0.01) reduced locomotor activity compared to vehicle (411 ± 35) and fenofibrate alone (388 ± 34). In parallel experiments, four groups of three adult male C57bl mice received a single injection of OEA (10 mg kg-1) or vehicle, and OEA levels in ileal tissue were quantified (Richardson et al., 2007). OEA levels were significantly elevated at 30 min (vehicle 0.49 ± 0.06; OEA, 18.97 ± 3.22 nmol g-1 of tissue; P<0.001) and 60 min (vehicle 2.48 ± 1.34; OEA, 17.22 ± 0.23; P<0.01), although levels of anandamide and 2-arachidonoylglycerol were unaltered at either timepoint (1-way ANOVA with Newman-Keuls test).

The different effects of OEA and fenofibrate administration suggest distinct mechanisms of action, while the extended duration of action of OEA with fenofibrate co-administration suggests a potentially novel indirect effect of PPARα receptors on food intake.

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