Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/13847
標題: 雷帕黴素阻礙高脂飼糧導致小鼠肥胖之研究
Study of the blockage effect of rapamycin in high fat diet-induced obesity mice
作者: 張耿瑞
Chang, Geng-Ruei
關鍵字: rapamycin
雷帕黴素
obesity
food intake
adipose tissue
leptin
肥胖
攝食量
脂肪組織
瘦體素
出版社: 獸醫學系暨研究所
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摘要: 雷帕黴素是由土壤中細菌- Streptomyces hygroscopicus分離出的一種抗黴菌藥,它同時也是mTOR的專一性抑制劑。由於雷帕黴素具有免疫抑制的特性,因此,近年來,雷帕黴素常廣泛使用於器官移植後,做為抗排斥藥物。雖然,已有文獻發現雷帕黴素具有抑制脂肪細胞分化的作用,然而,雷帕黴素對於是否具抗肥胖的效果仍不是十分清楚。本論文分別利用C57BL/6J及KK/HlJ 等2種不同品係的肥胖動物模式小鼠,探討雷帕黴素對於代謝的影響。肥胖C57BL/6J小鼠以雷帕黴素每週2 mg/kg劑量連續16週腹腔注射後,發現有體重、副睪脂肪重量減輕,減少每日飼料效率,血中瘦體素及胰島素濃度下降之情形。然而,雷帕黴素卻會增加C57BL/6J小鼠的食物攝取量,並且對於禁食血糖沒有顯著的影響。組織形態學分析每週一次腹腔注射雷帕黴素的C57BL/6J小鼠,其脂肪肝程度、脂肪細胞形態、大型後腹腔脂肪細胞和大型副睪脂肪細胞的比例皆顯著減小。於第二型糖尿病特徵KK/HlJ小鼠則改以雷帕黴素每天2 mg/kg劑量連續42天腹腔注射,結果發現雷帕黴素在KK/HlJ小鼠同樣具有抗肥胖效果。然而,注射雷帕黴素KK/HlJ小鼠即使有較高的胰島素濃度,但雷帕黴素卻會增加活性氧自由基的濃度,同時並造成KK/HlJ小鼠葡萄糖耐受性不良。綜合上述,雷帕黴素藉由減少脂肪蓄積而對抗高脂飲食會增加體重的效果,因此,雷帕黴素可用於體重控制和防止肥胖的發生,但長期、高頻率地使用雷帕黴素,仍需考慮其影響血糖恆定的副作用,特別是當用於高胰島素血症和葡萄糖耐受性不良之情形。
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.
URI: http://hdl.handle.net/11455/13847
其他識別: U0005-1908200915323300
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-1908200915323300
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