Heart is a resistin target tissue and heart can function as an autocrine organ. We sought to investigate whether cyclic mechanical stretch could induce resistin expression in cardiac myocytes and to test whether there is a linkage between the stretch-induced tumor necrosis factor- (TNF-) and resistin. Neonatal Wistar rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation at 60 cycles/min. Cyclic stretch significantly increased resistin protein and mRNA expression after 2 h to 18 h of stretch. Addition of PD98059, TNF- antibody, TNF- receptor antibody, and ERK MAP kinase siRNA 30 min before stretch inhibited the induction of resistin protein. Cyclic stretch increased, while PD98059 abolished the phosphorylated ERK protein. Gel shifting assay showed significant increase of DNA-protein binding activity of NF-B after stretch and PD98059 abolished the DNA-protein binding activity induced by cyclic stretch. DNA-binding complexes induced by cyclic stretch could be supershifted by p65 monoclonal antibody. Cyclic stretch increased resistin promoter activity while PD98059 and p65 antibody decreased resistin promoter activity. Cyclic stretch significantly increased the TNF- secretion from myocytes. Recombinant resistin protein and conditioned medium from stretched cardiomyocytes reduced glucose uptake in cardiomyocytes and recombinant siRNA of resistin or TNF- antibody reversed the glucose uptake. In conclusion, cyclic mechanical stretch enhances resistin expression in cultured rat neonatal cardiomyocytes. The stretch-induced resistin is mediated by TNF- at least in part, through ERK MAP kinase and NF-B pathways. Glucose uptake in cardiomyocytes was reduced by resistin upregulation.