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1 The central melanocortin system plays a key role in the regulation of food intake and energy homeostasis. We investigated whether genetic or pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in mice and rats with heart failure. Permanent ligation of the left coronary artery (MI), or sham operation was performed in wild-type (WT), or melanocortin-4 receptor knockout (MC4) mice. Eight weeks after surgery, WT-Sham mice had significant increases in lean body mass (LBM) (P < 0.05) and fat mass (P < 0.05), whereas WT-MI did not gain significant amounts of LBM or fat mass. Resting basal metabolic rate (BMR) was significantly lower in WT-Sham mice compared to WT-MI mice (P <0.001). In contrast, both MC4-Sham and MC4-MI mice gained significant amounts of LBM (P < 0.05) and fat mass (P < 0.05) over the study period. There was no significant difference in the BMR between MC4-Sham and MC4-MI mice. In the second experiment, rats received aortic bands, or sham operations and after recovery received intracerebroventricular injections of eithe