title: Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice.
abstract: Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance.
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Geng-Ruei
authors.initials: GR
authors.lastname: Chang
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wu
authors.forename: Yi-Shin
authors.initials: YS
authors.lastname: Chiu
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.forename: Jiunn-Wang
authors.initials: JW
authors.lastname: Liao
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Te-Hsin
authors.initials: TH
authors.lastname: Chao
authors.forename: Siu-Wan
authors.initials: SW
authors.lastname: Hung
authors.forename: Frank Chiahung
authors.initials: FC
authors.lastname: Mao
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D052436:Adipose Tissue, White / Q000187:drug effects; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D004041:Dietary Fats; D007166:Immunosuppressive Agents; D007328:Insulin; D020738:Leptin; D005947:Glucose; D020123:Sirolimus