Technical Abstract: The vagal afferent pathway is important in short-term regulation of food intake and decreased activation of this neural pathway with long-term ingestion of a high fat diet may contribute to hyperphagic weight gain. We test the hypothesis that expression of genes encoding receptors for orexigenic factors in vagal afferent neurons are increased by long-term ingestion of a high fat diet, thus supporting orexigenic signals from the gut. Obesity prone (DIO P) rats fed a high fat diet showed increased body weight and hyperleptinemia compared to low fat fed controls and high fat fed diet-induced obese resistant (DIO R) rats. Expression of the type I cannabinoid receptor and growth hormone secretagogue receptor in the nodose ganglia was increased in DIO P compared with low fat fed or DIO-R rats. Shifts in the balance between orexigenic and anorexigenic signals within the vagal afferent pathway may influence food intake and body weight gain induced by high fat diets.