Approximately half the male Sprague-Dawley rats fed a high energy diet develop diet-induced obesity (DIO). The remainder are diet-resistant (DR) and do not become obese. Resistance to DIO can be predicted before exposure to high energy diets by the presence of diminished norepinephrine (NE) release to an intravenous glucose load. Here chow-fed rats were prospectively placed in DR- or DIO-prone 'diet groups' by the areas under their glucose-induced (1 g/kg, i.v.) NE curves (DR rats less than 1200 pg/ml/60 min; DIO rats greater than 4500 pg/ml/60 min). To test the central pathways involved in the response to the intake of palatable foods, rats were first trained to drink 1 ml of 50% glucose within 1 min and then were tested for local cerebral glucose utilization using uptake of [14C]2-deoxy-D-glucose ([14C]2-DG) after receiving 0.15% sodium saccharin in place of glucose to avoid altering plasma glucose levels. Controls for basal cerebral metabolism (C) received no solution. DR-prone rats increased [14C]2-DG uptake by 60-190% in autonomic areas of the medulla (nucleus tractus solitarius, area postrema, dorsal motor nucleus X) and amygdala (central nucleus) in the S versus C conditions while DIO-prone rats had high basal levels of [14C]2-DG uptake in these areas and showed no increase after S. Also, DR-prone rats had 9-25% higher [14C]2-DG uptake in the ventromedial hypothalamic nucleus than DIO rats regardless of C or S conditions. Thus, pre-existing differences in the activation of autonomic areas of the brain in response to a food-related cue may be of etiological significance in the different patterns of food intake and weight gain seen in DR- and DIO-prone rats fed a high energy diet.