We examined whether manipulations of fat metabolism influence the feeding response to peripheral or central administration of 5-thio-D-glucose (5-TG), a potent inhibitor of glucose utilization. The increase in food intake produced by peritoneal (50 mg/kg) or fourth ventricular (50, 100, 150 micrograms) 5-TG was potentiated by administration of the fatty acid oxidation inhibitor, methyl palmoxirate (10 mg/kg, p.o.). In addition, rats maintained on a high-fat diet ate less in response to fourth ventricular 5-TG (150 micrograms) than did rats maintained on an equicaloric low-fat diet. These results suggest that the feeding response to 'glucoprivation' is determined by the interaction of glucose and fat oxidation.