During digestion, macronutrients are sensed within the small intestine. This sensory process is dependent upon the action of gut mediators such as cholecystokinin (CCK) or serotonin (5-HT) on vagal afferents that in turn convey peripheral information to the brain in order to influence the control of food intake. Recent studies have suggested that dietary conditions alter vagal sensitivity to CCK and 5-HT. This phenomenon may be of importance to the onset of eating disorders. The aim of the present study was thus to investigate the effects of subjecting mice to 15 days of either a high-fat diet (HF: 30% fat, 54% carbohydrate) or a normal fat diet (NF: 10% fat, 74% carbohydrate) on (i) daily and short term food intake, (ii) vagal sensitivity to peripheral anorectic factors and macronutrient loads and (iii) vagal afferent neuron receptor expression. The results indicated that compared to a normal fat diet, and while increasing food intake and body weight gain, a high fat diet altered the short term response to CCK-8 and intragastric macronutrient loads while decreasing vagal activation by CCK-8 and modifying the receptor expression of vagal neurons. These findings therefore suggest that dietary intervention effect on food intake could be linked to changes in vagal afferent receptor profiles.