Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

摘要

intraperitoneal injections of milligram doses of C75, an inhibitor of fatty acid synthase (FAS) that was originally developed for the treatment of cancer (21), dose-dependently decreased food intake in both mice and rats (10, 13,20, 25, 26, 39). Intracerebroventricular injections of C75 doses -3 log units smaller had similar effects (1, 2, 25), suggesting that C75 can act centrally to inhibit eating.In addition to its effect on FAS, C75 has other peripheral and central metabolic effects that might contribute to its eating inhibitory potency (2, 20, 22, 39, 43). One of these is the stimulation of carnitine palmitoyltransferase-1 (CPT-1) (2, 29,39). Increased CPT-1 activity stimulates fatty acid oxidation (FAO; 19), and several findings indicate that inhibition of peripheral FAO stimulates eating (11, 24, 36). There are some reports that administration of CPT-1 inhibitors into the central nervous system decreases food intake or body weight (31, 33). Recent findings, however, indicate that selective stimulation of CPT-1 activity in the brain is sufficient to inhibit eating and decrease body weight (2). First, the CPT-1-stimulatory action of C75 appears to contribute to the eating inhibitory effect of intracerebroventricular C75 because intracerebroventricular pretreatment with the CPT-1 inhibitor etomoxir attenuated the eating inhibitory effect of subsequent intracerebroventricular C75 injections (2). Second, intracerebroventricular injection of C89b, a novel compound that stimulates CPT-1 activity without affecting FAS activity, alone was sufficient to inhibit eat-ing (2).