The present study was designed to investigate (a) whether dietary fat manipulation, quantitatively and/or qualitatively, may influence the transport of fatty acids into the brain and oxidation of fatty acids in the hypothalamus; and (b) if an inhibitor of fatty acid oxidation changed food intake on these diets. Rats were fed for 4 wk 5% or 34% corn oil or tallow diets that were isocaloric and isonitrogenous. It was found that rats fed corn oil diets had significantly higher brain uptake index of palmitate than did rats fed tallow diets. In a second experiment, rats were fed either 30% corn oil or tallow diets and injected with either saline or mercaptoacetate (MA). Both saturated fat diets and mercaptoacetate injection reduced lateral hypothalamic, but not ventromedial hypothalamic fatty acid oxidation. Mercaptoacetate increased food intake only in the corn oil fed rats. It is proposed that these uptake and metabolic changes contribute to alterations in either energy expenditure or feeding behavior.