There is overwhelming evidence that a signal related to some aspect of energy metabolism is transduced in the liver and used to control food intake. However, it remains to be determined which biochemical event is transduced, how ingested and circulating fuels influence this event, and how the information derived from the liver is integrated with signals from other sites involved in the control of food intake. The project proposed here investigates these questions. The first goal will be to determine the nature of the effective stimulus provided by glucose in the hepatic portal vein. Mechanisms will be identified by comparing the effects of hepatic portal glucose infusions on food intake with (a) the distribution, hepatic uptake, and oxidation of infused glucose, (b) the duration of glucose infusion, and (c) the hepatic glucose gradient (portal-caval difference). The second goal will be to identify the biochemical events in the liver that control food intake. Specific metabolic pathways will be activated or inhibited using novel analogues of fructose. Comparison of behavioral results with in vivo and in vitro physiological measures will determine which metabolic pathways are critical for feeding behavior, and will also test the hypothesis that food intake is controlled by a signal generated by hepatic fuel oxidation. Finally, the hypothesis that fuel oxidation in the liver provides the stimulus for calorie-based conditioning (the acquired oral control of food intake) will be examined by comparing changes in food preference produced by substances that increase or decrease hepatic fuel oxidation.