AIMS: The farnesoid X receptor (FXR) is a member of the metabolic nuclear receptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodelling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodelling and dysfunction. METHODS AND RESULTS: Mice underwent either MI surgery or sham operation. At 1 week after MI, both sham and MI mice were gavaged with 25 mg/kg/d of a synthetic FXR agonist (GW4064) or a vehicle control for 7 weeks, and cardiac performance was assessed by consecutive echocardiography studies. Administration of GW4064 significantly increased left ventricular ejection fraction at 4 weeks and 8 weeks after MI (both P < 0.01). Moreover, GW4064 treatment increased angiogenesis and mitochondrial biogenesis, reduced cardiomyocyte loss and inflammation, and ameliorated cardiac remodelling as evidenced by heart weight, lung weight, atrial natriuretic peptide/brain natriuretic peptide levels, and myocardial fibrosis at 8 weeks post-MI. At the molecular level, GW4064 significantly increased FXR mRNA expression and transcriptional activity in heart tissue. Moreover, over-expression of myocardial FXR failed to exert significant cardioprotection in vivo, indicating that GW4064 improved post-MI heart remodelling and function independent of myocardial FXR expression/activity. Among the four down-stream soluble molecules of FXR, plasma adiponectin was most significantly increased by GW4064. In cultured adipocytes, GW4064 increased mRNA levels and protein expression of adiponectin. Conditioned medium of GW4064-treated adipocytes activated AMPK-PGC-1α signalling and reduced hypoxia-induced cardiomyocyte apoptosis, all of which were attenuated by an adiponectin neutralizing anti-body. More importantly, when knocking-out adiponectin in mice, the cardioprotective effects of GW4064 were attenuated. CONCLUSIONS: We are the first to show that FXR agonism ameliorated post-MI cardiac dysfunction and remodelling by stimulating adiponectin secretion. Thus, we demonstrated that FXR agonism is a potential therapeutic strategy in post-MI heart failure.