Increasing evidence suggests that the renin-angiotensin-system (RAS) contributes to the etiology of obesity. To evaluate the role of the RAS in energy and glucose homeostasis we examined body weight and composition, food intake and glucose tolerance in rats given the angiotensin-converting enzyme (ACE) inhibitor, captopril (40 mg/kg/day). Rats given captopril weighed less than controls when fed a high-fat diet (369.3±8.0 vs. 441.7±8.5 g after 35 days; p<0.001) or low-fat chow (320.1±4.9 vs. 339.8±5.1 g after 21 days; p<0.0001). This difference was attributable to reductions in adipose mass gained on high-fat (23.8±2.0 vs. 65.12±8.4 g after 35 days; p<0.0001) and low-fat diets (12.2±0.7 vs. 17.3±1.3 g after 21 days; p<0.001). Rats given captopril ate significantly less (3110.3±57.8 vs. 3592.4±88.8 kcal [cumulative 35-day high-fat diet intake]; p<0.001) despite increased in neuropeptide-Y mRNA expression in the arcuate nucleus of the hypothalamus and had improved glucose tolerance compared to free-fed controls. Comparisons to pair-fed controls indicated that decreases in diet-induced weight gain and adiposity and improved glucose tolerance were due, primarily, to decreased food intake. To determine if captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for two days. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that ACE inhibition protects against the development of diet-induced obesity and glucose intolerance.