Some of the actions of leptin depend on cholecystokinin (CCK). However, it is unknown whether leptin modulates the release of CCK. Here, we demonstrate in vitro that leptin induces the phosphorylation of extracellular signal-related kinase (ERK)-1/2 proteins and increases CCK release (EC(50) = 0.23 nmol/l) in CCK-secreting STC-1 cells. We showed that rat duodenal juice contains leptin that circulates free and bound to macromolecules, suggesting that leptin has a lumenal action on the intestine. In vivo in the rat, duodenal infusion of leptin increased plasma CCK at levels comparable to those induced by feeding. Moreover, meal-induced increases in plasma CCK were markedly reduced in obese fa/fa rats, whereas the mobilization of the gastric leptin pool was similar in lean and obese Zucker rats. The release of CCK by leptin presumably generates a positive feedback loop. Indeed, the blockade of CCK receptors reversed the meal reduction of the stomach leptin pool and the meal-increased plasma insulin, consistent with the previous concept of an entero-insular axis. Collectively, these data support a novel mode of action of leptin where leptin and CCK may potentiate their own effects by cross-stimulating their secretion. The impairment of this leptin-CCK loop may have pathological implications related to obesity and diabetes.