The effect of 2 days of oral dexamethasone administration (0.75 mg twice daily) on leptin expression in healthy volunteers was tested. Dexamethasone increased the relative abundance of leptin messenger RNA in abdominal and gluteal adipose tissues by approximately 70% (P < 0.05). Dexamethasone also significantly increased serum leptin (+ 80%) and insulin concentration (+ 83%) but did not affect serum glucose. We conclude that a hypercortisolemic/hyperinsulinemic state up-regulates leptin expression at the messenger RNA level in humans.