OEA exerts a number of pharmacological effects, including the induction of satiety, the reduction of body weight gain and the stimulation of lipolysis, through the activation of the peroxisome

The obesity epidemic continues to spread throughout the world, and the search for efficient therapies to combat obesity has become a priority for health systems (Stein and Colditz, 2004). However, the lack of drugs capable of reducing body weight gain without inducing adverse effects has led to a situation in which there is almost no available pharmacotherapy for obesity. The failure of the main classical central nervous system targets against obesity (i.e. serotonin transmission-based drugs or cannabinoid receptor antagonists) has prompted interest in the targeting of safer peripheral mechanisms controlling appetite and energy expenditure (Crespillo et al., 2011; de Fonseca, 2008). Among them, the anorectic lipid oleoylethanolamide (OEA) has been found to offer interesting properties for pharmaceutical development (Rodriguez de Fonseca et al., 2001; Fu et al., 2003). OEA is an acylethanolamide similar to the endocannabinoid anandamide (AEA), although AEA does not bind to or activate the cannabinoid CB1 receptor (Rodríguez de Fonseca et al., 2001). OEA is synthesised by a variety of cells, including astrocytes, neurons, enterocytes and adipocytes. In the small intestine, this lipid mediator is reduced by fasting and increased upon re-feeding in an opposite pattern to that exhibited by AEA (Fu et al., 2003; Gómez et al., 2002; Rodríguez de Fonseca et al., 2001). Its main role is to serve as a fat sensor, controlling fat intake and helping the metabolic network to adapt to the dietary fat load (Schwartz et al., 2008). OEA exerts a number of pharmacological effects, including the induction of satiety, the reduction of body weight gain and the stimulation of lipolysis, through the activation of the peroxisome proliferator-activated receptor alpha (PPAR) (Fu et al., 2003; Rodríguez de Fonseca et al., 2001). OEA binds to this nuclear receptor with high affinity, and its effects are absent in mice lacking PPAR (Fu et al., 2003). OEA reduces triglycerides and cholesterol, and, combined with a cannabinoid antagonist, blocks body weight gain and improves dyslipidaemia in animal models of obesity (Pavon et al., 2008; Serrano et al., 2008a). Additionally, the systemic administration of OEA has been found to modulate glucose homeostasis, as well as both insulin release (Ropero et al., 2009) and insulin signalling in both hepatocytes and adipocytes (González-Yanes et al., 2005; Martinez de Ubago et al., 2009). Although previous studies have reported that OEA actions are dependent on peripheral mechanisms, including the activation of sensory terminals and the release of gut peptides (Gómez et al., 2002; Rodríguez de Fonseca et al., 2001; Serrano et al., 2011), it has been recently described that the hypophagia observed after the