Effect Of Centrally Administered C75, A Fatty Acid Synthase Inhibitor, On Gastric Emptying And Gastrointestinal Transit In Mice

Objective:Fatty acid synthase(FAS)is the key enzyme that catalyzes the condensation of acetyl-CoA and malony-CoA to generate long-chain fatty acids in the cytoplasm.Recent studies indicated that central or systemic administration of 3-carboxy-4-octyl-2-methylenebutyrolactone(C75),a synthetic inhibitor FAS,causes anorexia and profound weight loss in rodents.It is well known that the amount of food intake and gastrointestinal mobility are closely related.In this study,an attempt has been made to investigate the effects and mechanisms of C75 on gastric emptying and gastrointestinal transit after intracerebroventricular(i.c.v.)injection in mice.Methods:We studied gastric emptying by using lyophilization method and gastrointestinal transit by using charcoal meal test method.The doses of 1,5,10μg/mouse were chosen to study the effects of C75 on gastric emptying and gastrointestinal transit.5-(tetradecyloxy)-2-furoic acid(TOFA,an acetyl-CoA carboxylase(ACC)inhibitor)and ghrelin were selected as functional antagonists to study the mechanisms involved in these process.Results:1.I.C.V.injection of C75(1,5,10μg/mouse)dose-dependently delayed gastric emptying and gastrointestinal transit in fasted mice.10μg C75 delayed gastric emptying by about 21.4%and reduced gastrointestinal transit by about 31.0%compared with vehicle control group.2.I.C.V.administration of TOFA almost fully reversed the delayed gastric emptying and gastrointestinal transit effects induced by 10μg C75.3.I.C.V.administration of ghrelin also significantly attenuated the delayed gastrointestinal mobility caused by 10μg C75.Conclusion:I.C.V.administration of C75 is able to decrease mice gastrointestinal mobility and it seems possible that the increased concentration of malonyl-CoA and decease concentration of ghrelin in hypothalamus might involve in these processes.