Study of the blockage effect of rapamycin in high fat diet-induced obesity mice

• Main Authors: Geng-Ruei Chang, 張耿瑞
• Other Authors: Frank Chiahung Mao
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/69688129014304382638

博士 === 國立中興大學 === 獸醫學系暨研究所 === 97 === Rapamycin (RAPA), an anti-fungal macrolide, is an unique and specific mTOR kinase inhibitor isolated from soil bacterium, Streptomyces hygroscopicus. Subsequently, RAPA was shown to have potent immunosuppressive and antiproliferative effects. As an immunosuppressant drug, it is used extensively to prevent graft rejection in transplant patients. Although, it has been reported to inhibit adipogenesis in vitro, however, the full extent of the role of RAPA in treating human/animal obesity has not been fully explored. In this study, we investigated the metabolic effects of RAPA in two different obese animal models, C57BL/6J and KK/HlJ mice. The high fat diet-fed (HFD) C57BL/6J mice were injected intraperitoneally with RAPA (2 mg/kg/week for 16 weeks) had reduced body weight and epididymal fat pads/body weight, reduced daily food efficiency, and lower serum leptin and insulin levels compared with the HFD control mice. However, RAPA-treated mice were hyperphagic, demonstrating an increase in food intake and exhibited similar blood glucose levels relative to the control group. Dissection of RAPA-treated mice revealed a marked reduction in fatty liver scores, average fat cell size and percentage of large adipocytes of retroperitoneal and epididymal white adipose tissue (RWAT and EWAT), compared to the HFD control mice. On the other hand, obese KK/HlJ mice were treated with a daily intraperitoneal injection of RAPA at 2 mg/kg or vehicle for 42 days on a HFD. Treated KK/HlJ mice also exhibited the pronounced anti-obesity effects of RAPA in metabolic parameters based on histological and image analysis. However, RAPA-treated animals showed a marked decline in glucose tolerance as judged by the 180-minute area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species (ROS), despite greater serum insulin levels. Tthese results suggest that RAPA preventsthe effect of a high fat diet on the rate of accretion in body weight via reducing lipid accumulation. It is likely that RAPA may serve as a potential strategy for body weight control and/or anti-obesity, while prolonged and continual use of RAPA can cause adverse effects such as the deterioration of blood glucose homeostasis, especially in conditions with hyperinsulinemia and glucose intolerance.