Rats maintained on a high-fat diet (HF) reduce their food intake less in response to intestinal infusion of oleic acid than rats maintained on a low-fat diet (LF). Inhibition of gastric emptying by intestinal infusion of oleate also is attenuated in rats fed a high-fat diet. It is well documented that intestinal oleate reduces food intake and inhibits gastric emptying via vagal sensory neurons. In addition, activation of intrinsic myenteric neurons participates in oleate-induced changes in gastrointestinal motility. To determine whether diminished behavioral and gastric reflex responses to intestinal oleate infusion is accompanied by reduced vagal sensory and myenteric neuronal activation, we examined expression of Fos-like immunoreactivity (Fos-li) in the dorsal hindbrains and the small intestinal enteric plexuses of rats maintained on HF or LF, following, intraintestinal infusion of oleate (0.06 kcal/ml) or the oligosaccharide, maltotriose (0.26 kcal/ml). Following oleate infusion there was a dramatic increase in the number of Fos-li nuclei in the NTS and AP of LF rats but not in HF rats. There also were significantly more Fos-li neuronal nuclei in the upper small intestinal submucosal and myenteric plexuses of the LF rats than the HF rats. In contrast to the effects of oleate infusion, maltotriose infusion significantly and similarly increased Fos-li nuclei in the hindbrains of both LF and HF rats. The results indicate that adaptation to high-fat diet selectively reduces vagal and enteric neuronal sensitivity to intestinal oleate and suggests that reduced sensitivity to the satiation and gastric inhibitory effects of oleate in high-fat fed rats may be mediated by a selective reduction in the neuronal response to intestinal stimulation by fatty acid.