Abstract 3769: Activation of PPAR-α Increases Adiponectin Expression and Attenuates Leptin-induced Hypertrophy in Rat Adult Cardiomyocytes
Leptin, a16 kDa peptide and a product of the obesity gene, has been shown to be elevated in patients with cardiovascular diseases including hypertension, coronary heart disease and heart failure. Cardiomyocytes synthesize leptin which in turn induces hypertrophy through autocrine-and paracrine-dependent process. Peroxisome proliferator-activated receptor-α (PPAR-α) is involved in regulation of lipid and energy metabolism in heart and its deletion or down regulation results in cardiac hypertrophy. In the present study we explored the role of PPAR-α and the adipokine adiponectin in antagonising leptin-mediated hypertrophy in cultured adult rat cardiomyocytes. Treatment of adult cardiomyocytes with leptin (3.1 nM) for 24 h enhanced cell surface area by 20% (P<0.05) and the hypertrophic marker gene α-skeletal actin, as measured by real-time PCR, by 400% (P<0.05). Since hypertrophy is associated with change in the utilization of energy substrates from fatty acids to glucose, we examined the effect of leptin on 14C-palmitate or 3H-deoxyglucose (DOG) uptake in cultured adult cardiomyocytes. Leptin treatment for 24 h decreased palmitate and increased DOG uptake in a concentration-dependent (0.31 to 12.4 nM) manner. The leptin-induced increase in cell surface area and α-skeletal actin gene expression was abrogated by the PPAR-α agonist oleoylethanolamide (OEA, 20 μM) which increased PPAR-α gene expression by 240% (P<0.05) following 24h treatment. In addition, treatment with OEA in presence or absence of leptin increased adiponectin protein expression by 44% (P<0.05) and 51% (P<0.05). Surprisingly, leptin increased the fatty acid translocase (FAT/CD36) gene expression by 44% (P<0.05) which was prevented by OEA. In contrast, OEA increased glucose transporter 4 (GLUT4) expression by 260% (P<0.05). Leptin had no direct effects on either PPAR-α, GLUT4 or adiponectin expression. This study shows that leptin-induced hypertrophy in adult cardiomyocytes is attenuated by PPAR-α activation possibly through a mechanism involving upregulation of adiponectin.