Cobaltic protoporphyrin IX (CoPP) is a synthetic heme analog which can elicit profound and prolonged decreases in appetite and body weight in several different animal species. Intracerebroventricular administration of CoPP in rats was found, by differential display and confirmed by Real-Time PCR, to result in an increase in expression of the creatine transporter when compared to vehicle-treated fed or vehicle-treated fasted control animals. In situ hybridization studies showed that creatine transporter mRNA concentrations were increased in several areas of the brain involved in the regulation of food intake, but creatine concentrations were decreased in hypothalamic homogenates in CoPP-treated animals compared to controls. Intracerebroventricular administration of beta-guanidinopropionic acid, a compound known to decrease intracellular creatine concentration by competition for uptake, resulted in decreased food intake and body weight and increased Fos expression in the hypothalamus. Taken together, these findings suggest that creatine concentrations in the brain may play a role in regulating food intake and body weight.