THE NEURAL CONTROL OF FOOD INTAKE and body weight is a complex function in which cognitive and emotional variables, as well as long-term signals of metabolic status and fuel storage, are integrated with short-term signals related to individual meals. Several years ago, Smith (20) proposed a useful classification of the myriad signals that influence the amount of food eaten during individual meals: direct controls, which arise from the interaction of ingested stimuli with receptors in the gastrointestinal tract; and indirect controls, which comprise all other controls of food intake, including signals pertaining to the status of body fat stores, such as leptin and insulin. According to this model, indirect controls affect meal size by increasing or decreasing the potency of direct controls. Early support for this concept was supplied by Woods and colleagues (7, 19), who showed that infusion of insulin into the brain increases sensitivity to the gut-derived “satiety factor” cholecystokinin (CCK), and similar interactions between CCK and other indirect controls, including leptin and estrogen, have since been documented (2, 4, 5). An important strength of this model is the framework it provides for identifying the neural circuits that detect and integrate these direct and indirect signals. It is widely accepted that excitatory gustatory and inhibitory gastrointestinal feedback, major determinants of meal size, are relayed to the brain through cranial nerve nuclei in the caudal brain stem. Taste information supplied by the facial, glossopharyngeal, and vagus nerves is first processed by the nucleus of the solitary tract (NTS)(21), and relevant visceral sensory information, such as gastric and intestinal distension or the release of CCK, is relayed to the central nervous system (CNS) through vagal afferents that synapse in the same hindbrain area (15). Indirect controls of food intake are more diverse and do not enter the brain through a single afferent route. The adipocyte-derived hormone leptin is an important example of an indirect control that communicates information regarding body energy stores to the brain. Leptin circulates at levels proportionate to body fat mass, crosses the blood-brain barrier, binds to its receptors on neurons in key brain areas for food intake control, and in so doing ultimately favors the consumption of smaller meals (8). The concept that leptin action in the forebrain reduces meal size by enhancing the hindbrain response to gastrointestinal satiety signals has recently received direct experimental support (16).