Corticotropin-releasing factor (CRF) receptor agonist and CRF binding-protein (CRF-BP) ligand inhibitor peptides both activate CRF systems but exert very distinct functional profiles in animal models of arousal, energy balance and emotionality. The present studies were designed to extend the dissimilar efficacy profiles of central administration of a CRF agonist, r/h CRF(1-41), versus a CRF-BP ligand inhibitor, r/h CRF(6-33), into mouse and rat models of energy balance in order to further explore in vivo efficacy of these ligands in two separate animal species. In CD-1 mice, food intake was significantly attenuated 3 h after acute administration of CRF(1-41) (0.007-0.2 nmol), but not CRF(6-33). In obese Ob/Ob mice, both CRF(1-41) (0.007-0.2 nmol) and CRF(6-33) (0.02-2.3 nmol) significantly attenuated basal feeding over 3 h following acute peptide administration. In rats, CRF(1-41) (1 nmol) and CRF(6-33) (1.5-7.7 nmol) infusion significantly increased rectal temperature. In studies employing a telemetry apparatus, core temperature was also increased by CRF(1-41) (1 nmol) and CRF(6-33) (1.5 nmol), whereas only CRF(1-41) increased locomotor activity and heart rate. These results suggest that CRF receptor agonist administration is capable of producing a global profile of negative energy balance by reducing food intake in mice and increasing energy expenditure in rats. In contrast, CRF-BP ligand inhibitor administration appears to suppress food intake in a mouse strain selective manner and to elevate rectal and core temperature in rats without accompanying cardiovascular activation.