Leptin (Ob protein) is a recently isolated hormone produced by adipocytes and is a powerful regulator of satiety centers in the brain. A defect in either leptin production or transmission of the leptin signal in animal models, i.e.ob/obanddb/dbmice, respectively, results in a syndrome of obesity and diabetes which closely resembles that which occurs in humans. Leptin release is regulated in part by nutritional status and its expression in adipose tissue is up-regulated by insulin. Since hyperinsulinemia is a primary defect inob/obanddb/dbmice which manifests early in the disease, we postulated that leptin may also regulate insulin release as part of a ‘adipoinsular’ feedback loop. We demonstrate the expression of leptin receptor mRNA in primary rat pancreatic islets and in the insulinoma cell line βTC-3. Furthermore, we find binding of¹²⁵I-leptin to βTC-3 cells which is significantly displaced by leptin. These findings suggest the possibility that the binding of leptin to its receptor in β-cells may modulate insulin expression in a negative feedback loop, and thereby may have an anti-obesity effect.