The aim of this experiment was to investigate whether the anorectic effect of apolipoprotein A-IV (apo A-IV) after lipid feeding is mediated via the central nervous system. Infusion of 0.5 micrograms of apo A-IV into the third ventricle failed to suppress food intake. Higher doses (1 micrograms or higher) of apo A-IV infused into the third ventricle inhibited food intake in a dose-dependent manner. In contrast, when apo A-I was infused into the third ventricle it had no effect on food intake. To further test the hypothesis that apo A-IV is an important factor controlling food intake, we administered goat anti-rat apo A-IV serum into the third ventricle of rats that were allowed food and water and lib. In all rats tested, this treatment resulted in enhanced food intake. In contrast, infusion of goat anti-rat apo A-IV serum failed to elicit such a response. Lastly, we determined the apo A-IV concentration in plasma and cerebrospinal fluid before and during active lipid absorption. Apo A-IV concentration in cerebrospinal fluid was about 1/20 that of plasma. Both serum and cerebrospinal fluid apo A-IV increased markedly as a result of feeding of lipid. In conclusion, we propose that apo A-IV may act centrally to control food intake.