Deficiency of adiponectin (APN), a cardioprotective adipokine, as a risk factor of cardiovascular disease is well-defined. Recent clinical studies report that plasma APN levels are increased in heart failure (HF) patients, suggesting APN resistance might be another unrecognized risk factor. However, direct evidence supporting cardiac APN resistance during HF progression is currently lacking. Adult male mice were subjected to HF by coronary artery occlusion. The biological functions of APN were determined during the course of HF development (0-6 weeks). Plasma APN levels were reduced 3 days post-MI (P<0.01), gradually recovered thereafter, and reached a level greater than control 14 days post-MI (P<0.05). Consistent with APN level reduction, cardiac AMPK phosphorylation (a readout of APN intracellular signaling) was decreased 3 days post-MI (P<0.05). However, cardiac AMPK phosphorylation remained lower than control 14 days post-MI (P<0.01), despite significantly increased plasma APN levels at this time, suggesting reduced cardiac response to endogenous APN. APN administration via osmotic pump beginning 14 days post-MI for the remaining duration of MI did not protect against MI/R injury, in contrast to numerous previous studies demonstrating the cardioprotective effects of APN in acute MI/R. At the molecular level, APN treatment significantly increased both GLUT4 membrane recruitment and 18 F-FDG uptake in the normal heart (P<0.01). However, these responses were dramatically reduced 14-days post-MI. To gain more direct evidence demonstrating impaired cardiomyocyte response to APN during HF development, left ventricular cardiomyocytes were isolated from normal or MI mice (14 days), and incubated with human recombinant APN. APN-induced AMPK phosphorylation and PKA activation were significantly reduced in CM from MI mice compared to control (P<0.01). Together, these results demonstrate that APN resistance develops 2 weeks after MI, a critical period when the transition from adaptive to pathological remodeling occurs. APN resistance renders a potent endogenous cardioprotective molecule ineffective, thus facilitating HF progression. Interventions restoring cardiac APN response may be a novel approach against post-MI HF development.