Anorexic response to rapamycin does not appear to involve a central mechanism

• Published in: Clinical and experimental pharmacology & physiology 2016-09, Vol.43 (9), p.802-807
• Main Authors: Toklu, Hale Z., Bruce, Erin B., Sakarya, Yasemin, Carter, Christy S., Morgan, Drake, Matheny, Michael K., Kirichenko, Nataliya, Scarpace, Philip J., Tümer, Nihal
• Format: Article
• Language: English
• Subjects: aging; Animals; Anorexia - drug therapy; Anorexia - metabolism; Anorexia - physiopathology; Body Weight - drug effects; brain; central; Eating - drug effects; Energy Intake - drug effects; grip strength; HOMA-IR; hypothalamus; intracerebroventricular; leptin; locomotor; mTOR; pS6; rapamycin; Rats; Sirolimus - pharmacology; Sirolimus - therapeutic use; Treatment Outcome
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.12601

Summary The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes‐like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23–25‐month‐old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.