Since mice with a deletion of the neurotrophin-4 (NT-4) gene exhibit a loss of both nodose ganglion neurons and vagal afferent terminals in the small intestines, we hypothesized that the reduced intestinal innervation of the NT-4 knock out (NT-4KO) mouse would lead to a corresponding reduction in the pre-absorptive feedback from macronutrients. To explore this prediction, we measured meal patterns in NT-4KOs and controls while, on different days, intragastric infusions of either lipids (Intralipid; 10%, 20%) or glucose (12.5%, 25%) were yoked to each animal’s spontaneous feeding of a pelleted diet (~ 1 kcal infused/1 kcal ingested). NT-4KO mice were relatively, though not completely, insensitive to the lipid infusions, whereas they were as sensitive as controls to glucose infusions. More specifically, the regulatory deficits of NT-4KOs included (1) attenuated satiation from the lipid infusions, as measured by smaller intra-meal reductions of both meal size and meal duration, (2) defects in satiety associated with the fat infusions, as measured by smaller inter-meal increases of both satiety ratio and inter-meal interval, and (3) losses in daily compensatory responses for lipid calories. These results support the hypothesis that NT-4KO mice have deficits in macronutrient feedback from the GI tract, indicate that the defects are specific insofar as they do not include impairments in the feedback of glucose infusions on feeding, and suggest that early feedback about dietary lipids is important in the regulation of satiation, satiety, and longer-term compensation of daily caloric intake.