Glucose, 2-deoxyglucose, phlorizin, and insulin were injected into the third ventricle of lean and fatty rats, and food intake recorded hourly for the next 6 h. In the lean rats, there was a significant but unimpressive decrease in food intake after the intraventricular injection of glucose, but there was no effect of glucose in the fatty rat. Phlorizin in the lowest dose (10 micrograms) increased the food intake in lean animals at 1 and 2 h, and all three doses increased it significantly at 6 h after intraventricular injection. The fatty rat, in contrast, showed no response to phlorizin. 2-Deoxyglucose showed a dose-related stimulation of food intake in the lean rats at 1, 2, 3, and 6 h after injection. In the fatty rat, there was no significant effect on food intake at any dose. The intraventricular injection of insulin had no effect on food intake in either the lean or fatty rats. These studies indicate that glucose-responding systems in the region of the third ventricle are defective in the fatty rat to signals that normally increase or decrease food intake in lean animals.