Many gastrointestinal meal-related signals are transmitted to the central nervous system via the vagus nerve and thereby control changes in meal size. c-fos positive neuron has been used as a marker of neuronal activation after lipid meals to examine the contribution of a selective macronutrient on brain neuro-circuit activity. In rats fed Intralipid, the c-fos positive neurons were highly stimulated in the nucleus of the solitary tract (NTS), and in the hypothalamus, including paraventricular nucleus (PVN), arcuate nucleus of the hypothalamus (ARC) and ventromedial hypothalamus (VMH) at 4 hr-lipid feeding. However, c-fos-like immunoreactivity was markedly attenuated in these brain regions when chylomicron formation/secretion was blocked by Pluronic L-81 (L-81). After lymph was diverted from the lymph cannulated animals, the rats had lower number of c-fos positive cells in the NTS and ARC. In contrast, the rats had a higher c-fos positive neurons in PVN. The present study also revealed that c-fos positive neurons induced by feeding of Intalipid were abolished by cholecystokinin type 1 (CCK1) receptor antagonist, Lorglumide. We conclude that the formation and/or secretion of chylomicron are critical steps for initiating neuronal activation in the brain.