Mice respond to fatty acid synthase (FAS) inhibitors by profoundly reducing their food intake and body weight. Evidence indicates that the central nervous system (CNS) may be the critical site of action; however, a peripheral contribution cannot be ruled out. We compared doses of the FAS inhibitor C75 in the CNS (third ventricle [i3vt]) and periphery (intraperitoneal [IP]) to reduce food intake and body weight in rats. Centrally, the threshold dose was 3 micro g, whereas a dose of 10 mg/kg was required peripherally. Such data argue for FAS activity in the CNS as a potent target for the actions of C75. To control for nonspecific effects of FAS inhibition, we compared C75 administration in two models of illness, conditioned taste aversion and need-induced sodium appetite. Our results suggest the anorexia produced by IP C75 is accompanied by visceral illness, whereas the anorexia produced by i3vt is not. In addition, we placed animals in an indirect calorimeter after an IP injection of C75. We found that consistent with behavioral measures of visceral illness, peripheral C75 reduced heat expenditure and resulted in animals losing less weight than fasted control animals, suggesting that peripherally administered C75 has aversive properties. Understanding the mechanisms by which FAS inhibition in the CNS reduces food intake could lead to specific targets for the manipulation of energy balance and the treatment of obesity.