In humans, higher cortisol responses to stress coincides with increased food intake1 . We have identified sub-populations of ewes that have either high (HR) or low (LR) cortisol responses to ACTH (10% from each extreme). When placed on a high energy diet, HR have a greater increase in adiposity than LR, which is not due to different food intake but is associated with reduced post-prandial thermogenesis in skeletal muscle2 . Hypothalamic appetite-regulating peptides (ARP) exert reciprocal effects on food intake and energy expenditure/thermogenesis. The main aim of this study was to characterise differences in expression and function of ARP in HR and LR ewes. In situ hybridization (n=4/group) was used to quantify the expression of genes for neuropeptide Y (NPY) proopiomelanocortin (POMC), melanocortin receptors (MC3R & MC4R), orexin and melanin-concentrating hormone (MCH). Expression of NPY and POMC was similar in LR and HR, but LR had higher levels of expression of MCH (P<0.05), orexin (P<0.01) MC3R (P<0.05) and MC4R (P<0.001). Intracerebroventricular (icv) infusions (N=6/group, 1000-1600h) of NPY (50µg/h), α-melanocyte stimulating hormone (αMSH), orexin and MCH were performed in ewes entrained to a daily meal feeding (food available between 1100-1600h). Post-prandial thermogenesis in muscle was higher (P<0.05) in LR. The temperature response to MCH infusion was lower in LR than in HR, with no effect of NPY, αMSH or orexin infusion. NPY, MCH and orexin did not stimulate food intake in meal-fed animals and αMSH reduced food intake (P<0.01) in LR only. With 24h infusions, NPY increased (P<0.001) food intake in both groups but αMSH was only effective in LR (P<0.05). We conclude that HR are resistant to the satiety effects of αMSH and this is most likely due to reduced expression of MC3R and MC4R. Thus, the higher propensity of HR to become obese is associated with reduced melanocortin signalling.