Leptin has significant effects on appetite, energy expenditure, lipid mobilisation and reproduction. During pregnancy, leptin is produced in the placenta, a tissue in which leptin receptors are highly expressed, suggesting autocrine/paracrine functions for this hormone. In the present study, a putative role of leptin as a regulator of nitric oxide (NO) production and lipid metabolism was evaluated in term human placenta. We demonstrated that leptin enhanced NO production in human placental explants (P < 0.01). Although leptin did not modify the placental levels of cholesteryl esters and phospholipids, leptin decreased levels of triglycerides (P < 0.01) and cholesterol (P < 0.001) in term human placenta. The effect of leptin on lipid mass seems to be independent of the modulation of de novo lipid synthesis because leptin did not modify the incorporation of (14)C-acetate into any of the lipids evaluated. We investigated the effects of leptin on placental lipid catabolism and found that in both term human placental explants and primary cultures of trophoblastic cells, leptin increased glycerol release, an index of the hydrolysis of esterified lipids, in a dose-dependent manner. In conclusion, we have shown that leptin affects NO production and lipid catabolism in human placenta, providing supportive evidence for a role of leptin in placental functions that would determine the transfer of nutrients to the developing fetus.