The present study was designed to evaluate the cardioprotective effects of nesfatin-1, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3 beta signaling pathway in the protective effect of nesfatin-1. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85 mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p-Akt/Akt and p-GSK3 beta/GSK-3 beta significantly decreased in heart tissue after ISO -induced MI. However, intraperitoneal administration of nesfatin-1 (10 mu g/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of nesfatin-1 against ISO-induced ML The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p-Akt/Akt and p-GSK-3 beta/GSK-3 beta in the myocardium of MI group rats were significantly increased by nesfatin-1 administration, suggesting that nesfatin-1, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO induced MI via an Akt/GSK-3 beta-dependent mechanism.