We previously reported an exaggerated endocrine and weight loss response to stress in rats fed high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on HF-diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and non-obese HF-fed rats. Third ventricle infusion of corticotrophin releasing factor (CRF) in rats made obese on HF-diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF₂ receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed LF-diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF1 receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF-diet for five days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (i.p. saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF-diet for five days due to a non-significant increase in expression in non-stressed HF-fed rats. In addition, non-stressed levels of UCN I mRNA expression in the Edinger Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on HF-diet show a change in responsiveness to stress peptides, whereas the increased stress-response in non-obese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.