One of the major manifestations of obesity is increased production of the adipocyte-derived 16-kDa peptide leptin, which is also elevated in heart disease, including congestive heart failure. However, whether leptin can directly alter the cardiac phenotype is not known. We therefore studied the effect of leptin as a potential hypertrophic factor in cultured myocytes from 1- to 4-day-old neonatal rat heart ventricles. Using RT-PCR, we demonstrate that these cells express the short-form (OB-Ra) leptin receptor. Twenty-four hours of exposure to leptin (0.31 to 31.3 nmol/L) produces a significantly increased cell surface area that peaked at 0.63 nmol/L. Subsequent experiments were done with 3.1 nmol/L leptin, which significantly increased cell area by 42%, protein synthesis by 32%, and alpha-skeletal actin and myosin light chain-2 expression by 250% and 300%, respectively. These events occurred in the absence of any increased cell death. Hypertrophy was preceded by rapid activation of the mitogen-activated protein kinase system including p38 and p44/42 as early as 5 minutes after leptin addition, whereas hypertrophy was inhibited by the p38 inhibitor SB203580 but not by the p44/42 inhibitor PD98059. Our results demonstrate a direct hypertrophic effect of leptin and may offer a biological link between hypertrophy and hyperleptinemic conditions such as obesity.