Leptin is an important hormone that has potent effects on appetite and body weight. The regulation of leptin gene expression and secretion by corticosteroids and insulin was studied in the rat. Adrenalectomy resulted in a significant reduction in leptin gene expression and secretion. The reduction was corrected by hormonal replacement with corticosterone pellets, showing that normal levels of circulating corticosteroids are required to maintain leptin expression and secretion in the body. Chronic treatment with dexamethasone (DEX) over 3 wk did not significantly increase leptin gene expression and secretion, contrary to earlier reports using shorter treatment paradigms. The profound weight loss associated with chronic DEX treatment may have abrogated the direct stimulatory effect of DEX on leptin gene expression and secretion, indicating a possible crosstalk between corticosteroids and leptin in the regulation of body weight. Shorter-term treatment of animals with DEX (3.7 micrograms/g body wt; 24 h) increased leptin gene expression and secretion about 2-fold and 1.4-fold, respectively. The increase was independent of circulating insulin concentrations. In streptozotocin-treated rats, short-term DEX treatment increased leptin gene expression and secretion about 3.5-fold and 2-fold, respectively. The data indicate that circulating leptin concentrations and adipose tissue leptin expression are dependent on corticosteroids and insulin. Although acute DEX treatment resulted in a stimulatory effect on leptin secretion and expression, chronic DEX treatment did not. The stimulatory effect of DEX on leptin is independent of circulating insulin concentrations.