Leptin, an important adipose-derived hormone, is recognized as a crucial protein in energy homeostasis. Recent studies indicated that leptin is associated with cardiac pathophysiology, however, the role and mechanisms of leptin in cardiomyocytes apoptosis are poorly understood. Here we investigated whether leptin exerted protective effect on cardiomyocytes exposed to tumor necrosis factor-alpha (TNF-alpha) and the possible mechanisms. Neonatal rat cardiomyocytes were subjected to TNF-alpha in the presence or absence of leptin. By FITC/Annexin V flow cytometry and Western blot, we noticed that TNF-alpha increased Annexin V binding and cleaved caspase-3/PARP, which were attenuated by leptin pretreatment. Moreover, leptin protected cardiomyocytes against mitochondrial apoptosis by inhibiting cytochrome C elevation and Bcl-2 decreasing. TNF-alpha-induced P38 MAPK and NF-kappa B activation were abolished by leptin addition, and the P38 and NF-kappa B inhibitor, SB203580 and 8ay117082, also mitigated the apoptotic effect of TNF-alpha, indicating that their activation might be responsible for the apoptosis in TNF-alpha-treated cardiomyocytes. Therefore, leptin conferred anti-apoptotic effect in cardiomyocytes exposed to TNF-alpha possibly by inhibiting TNF-alpha-activated P38 MAPK and NF-kappa B pathways. (C) 2014 Published by Elsevier Inc.