The mechanisms through which leptin, the protein product of the ob gene, affects food intake remain to be determined. To assess whether the actions of leptin depend on modulation of within-meal satiety signals, we measured the effect of third ventricular leptin administration on the satiety actions of CCK. Leptin (10 μg) administered 1 h before 30-min access to a liquid diet had no effect on intake when administered alone, but doses of 3.5 or 10 μg dose dependently increased the suppression of intake produced by 1 nmol/kg CCK. Examination of patterns of c-Fos activation induced by 3.5 μg leptin and 1 nmol/kg CCK revealed that the combination produced significant c-Fos activation within the area postrema and the caudal and medial nucleus of the solitary tract (NST) compared with either leptin or CCK treatments alone. The leptin-CCK combination also resulted in increased c-Fos activation within the paraventricular nucleus of the hypothalamus above that produced by leptin alone. These data suggest that the actions of leptin in food intake are mediated through its ability to modulate responsivity to within-meal satiety signals.

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Feedback signals arising from the oral cavity and upper gastrointestinal tract contribute to the control of meal size. To assess how these signals are integrated at central sites involved in ingestive control, we compared levels of c-Fos activation in the nucleus of the solitary tract (NTS) and area postrema (AP) in response to meal ingestion or gastric and duodenal infusions in the rat. Ingestion of a liquid diet to satiety induced significant fos-like immunoreactivity (FLI) at multiple levels of the NTS and within the AP. The restriction of intake to one-half the normal ingestion of a rat did not result in significant FLI, although gastric infusion of this liquid diet volume did. Fast bolus infusion resulted in greater FLI than did the same volume infused at a rate to mimic that of normal ingestion. Prior experience with gastric infusions did not affect the amounts of FLI within the NTS or AP. In rats with pyloric cuffs blocking flow from the stomach to the intestine, combined gastric load and duodenal nutrient elicited significantly greater FLI than either gastric or duodenal infusions alone. These data demonstrate that neural activation arising from meal-related stimuli are integrated at the level of the NTS.