The ongoing oleoylethanolamide story: Therapeutic implications in the control of obesity and its comorbidities.

The global burden of obesity continues to rise, demanding effective pharmacological strategies for individuals in whom prevention alone is insufficient. Recent incretin-based and multi-agonist therapies have delivered unprecedented weight loss, demonstrating that the simultaneous modulation of multiple metabolic pathways can optimize body weight control and improve obesity-related comorbidities. However, biological heterogeneity, interindividual variability in treatment response and uncertainties regarding long-term outcomes highlight the need to explore complementary regulatory mechanisms. Oleoylethanolamide (OEA) is an endogenous lipid mediator synthesized on demand in the small intestine in response to dietary lipid intake. Acting primarily through peroxisome proliferator-activated receptor-α (PPAR-α), OEA functions as a physiological satiety signal that promotes fatty acid oxidation and coordinates gut-brain communication. Preclinical evidence indicates that OEA reduces food intake without inducing malaise, enhances lipid utilization and improves metabolic dysfunction in models of diet-induced obesity, while engaging both homeostatic and reward-related neural circuits. Emerging clinical studies report modest but consistent effects on body weight and selected cardiometabolic parameters. In this review, we summarize the current evidence on OEA biosynthesis, molecular targets and mechanisms of action, with particular focus on its role in the regulation of feeding behaviour, metabolic homeostasis and obesity-related comorbidities, and discuss its potential positioning within the evolving landscape of anti-obesity pharmacotherapy.