Role of endocannabinoids and their analogues in obesity and eating disorders.

Fatty acids ethanolamides (FAEs) are a family of lipid mediators. A member of this family, anandamide, is an endogenous ligand for cannabinoid receptors targeted by the marijuana constituent Delta-9-tetrahydrocannabinol. Anandamide is now established as a brain endocannabinoid messenger and multiple roles for other FAEs have also been proposed. One emerging function of these lipid mediators is the regulation of feeding behavior and body weight. Anandamide causes overeating in rats because of its ability to activate cannabinoid receptors. This action is of therapeutic relevance: cannabinoid agonists are currently used to alleviate anorexia and nausea in AIDS patients, whereas the cannabinoid receptor CB1 antagonist rimonabant was recently found to be effective in the treatment of obesity. In contrast to anandamide, its monounsatured analogue, oleoylethanolamide (OEA), decreases food intake and body weight gain through a cannabinoid receptor-independent mechanism. In the rat proximal small intestine, endogenous OEA levels decrease during fasting and increase upon refeeding. These periprandial fluctuations may represent a previously undescribed signal that modulates between-meal satiety. Pharmacological studies have shown, indeed, that, as a drug, OEA produces profound anorexiant effects in rats and mice, due to selective prolongation of feeding latency and post-meal interval. The effects observed after chronic administration of OEA to different animal models of obesity, clearly indicate that inhibition of eating is not the only mechanism by which OEA can control energy metabolism. In fact, stimulation of lipolysis is responsible for the reduced fat mass and decrease of body weight gain observed in these models. Although OEA may bind to multiple receptors, several lines of evidence indicate that peripheral PPAR-alpha mediates the effects of this compound. The pathophysiological significance of OEA in the regulation of eating and body weight is further evidenced by preliminary clinical results, showing altered levels of this molecule in the cerebrospinal fluid and plasma of subjects recovered from eating disorders. These results complete previous observation on anandamide content, which resulted altered in plasma of women affected by anorexia nervosa or binge-eating disorder.