title: Anorexic response to rapamycin does not appear to involve a central mechanism.
abstract: 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.
authors.affiliation: Veterans Affairs Geriatric Research Education & Clinical Center, Gainesville, FL, USA.|Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Hale Z
authors.initials: HZ
authors.lastname: Toklu
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Bruce
authors.affiliation: Veterans Affairs Geriatric Research Education & Clinical Center, Gainesville, FL, USA.|Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Sakarya
authors.affiliation: Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
authors.forename: Christy S
authors.initials: CS
authors.lastname: Carter
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Matheny
authors.affiliation: Veterans Affairs Geriatric Research Education & Clinical Center, Gainesville, FL, USA.|Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kirichenko
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Scarpace
authors.affiliation: Veterans Affairs Geriatric Research Education & Clinical Center, Gainesville, FL, USA.|Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Tümer
mesh_terms: D000818:Animals; D000855:Anorexia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D002149:Energy Intake / Q000187:drug effects; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020123:Sirolimus
keywords: HOMA-IR; aging; brain; central; grip strength; hypothalamus; intracerebroventricular; leptin; locomotor; mTOR; pS6; rapamycin