Oleylethanolamide (OEA), a naturally occurring lipid, regulates satiety and body weight. This study demonstrates that OEA binds with high affinity to the nuclear receptor peroxisome-proliferator-activated receptor-α (PPAR-α), which is involved in lipid metabolism. Administration of OEA reduces food intake and body weight gain in wild-type mice but not in PPAR-α-deficient mice. Two distinct PPAR-α agonists produce similar effects, while PPAR-γ and PPAR-β/δ agonists are ineffective. OEA regulates the expression of PPAR-α target genes in the small intestine, including those involved in lipid metabolism and iNOS, an enzyme that may contribute to feeding stimulation. OEA also reduces serum cholesterol and triglyceride levels in genetically obese rats. These findings suggest that OEA acts as an endogenous PPAR-α agonist, mediating its satiety and weight-regulating effects through activation of PPAR-α. The study highlights the potential of OEA as a therapeutic target for eating disorders.Oleylethanolamide (OEA), a naturally occurring lipid, regulates satiety and body weight. This study demonstrates that OEA binds with high affinity to the nuclear receptor peroxisome-proliferator-activated receptor-α (PPAR-α), which is involved in lipid metabolism. Administration of OEA reduces food intake and body weight gain in wild-type mice but not in PPAR-α-deficient mice. Two distinct PPAR-α agonists produce similar effects, while PPAR-γ and PPAR-β/δ agonists are ineffective. OEA regulates the expression of PPAR-α target genes in the small intestine, including those involved in lipid metabolism and iNOS, an enzyme that may contribute to feeding stimulation. OEA also reduces serum cholesterol and triglyceride levels in genetically obese rats. These findings suggest that OEA acts as an endogenous PPAR-α agonist, mediating its satiety and weight-regulating effects through activation of PPAR-α. The study highlights the potential of OEA as a therapeutic target for eating disorders.