In the hypothalamic arcuate nucleus, neurones that coexpress cocaine-amphetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone [alpha-MSH; pro-opiomelanocortin (POMC) derived] peptides exert catabolic actions and are stimulated by leptin. However, leptin treatment also affects other circulating factors that influence hypothalamic gene expression. Notably, the hypercorticosteronaemia of ob/ob mice is lowered by leptin treatment. To examine the interaction between glucocorticoids and leptin on POMC/CART mRNA expression, an experiment combining leptin and adrenalectomy (ADX) in leptin deficient ob/ob mice was carried out. Obese ob/ob and lean littermate Ob/? mice were ADX or sham-operated. ADX mice received a pellet containing 25% corticosterone subcutaneously. Seven days postoperatively, mice were injected intraperitoneally for 5 days with either recombinant human leptin or vehicle. On the sixth day, the mice were decapitated and the brains removed and trunk blood was collected for corticosterone analysis. Plasma concentrations of corticosterone were elevated in all ob/ob groups compared to Ob/?. For both ob/ob and Ob/? groups, corticosterone concentrations exhibited a decline across groups: vehicle-sham>leptin-sham>ADX-vehicle>ADX-leptin. Leptin inhibited food intake and bodyweight in ob/ob-sham and ob/ob-ADX to a similar extent, whereas no effect of leptin was observed in Ob/? mice. Similarly, leptin caused an identical increase in arcuate POMC and CART mRNA expression in ob/ob-sham and ob/ob-ADX compared to vehicle. The present data support the view that leptin influences arcuate POMC and CART mRNA expression directly, and that the effect is not modulated by corticosterone across a wide range of circulating corticosterone concentrations.