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The effects of rapamycin on olanzapine induced obesity in C57BL/6JNarl mice
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奧氮平 (olanzapine)為一非典型抗精神病藥物，然服用後卻易導致體重增加與肥胖。研究證實抑制mTOR pathway有助於減重及維持血糖恆定，而雷帕黴素 (rapamycin)為mTOR激酶之抑制物。本研究使用C57BL/6JNarl小鼠，分控制組、奧氮平組 (3 mg/kg/day)、雷帕黴素組 (2 mg/kg/day)及奧氮平合併使用雷帕黴素組，連續給予7週。研究結果顯示奧氮平組體重增加高於控制組 (p<0.01)；而雷帕黴素之給予於第3~5週可有效抑制奧氮平導致之體重增加 (p<0.05)。然而分析各組肝臟及腹腔脂肪組織切片，顯示其空胞化程度並無明顯差異。以西方墨點法分析肝臟組織中之stearoyl-CoA desaturase-1 (SCD-1)含量，顯示奧氮平似乎有增加SCD-1表現量之趨勢。另外，給予奧氮平組之小鼠有較高的攝食量、雷帕黴素組則較低；血清瘦體素方面，給予奧氮平之小鼠為最低，而雷怕黴素組最高。由上述結果推論給予奧氮平可使血清瘦體素濃度降低，增加攝食量而導致肥胖；雷帕黴素則藉由抑制mTOR pathway增加血清瘦體素濃度，減少攝食量而抑制體重之增加。本研究結果或能提供奧氮平導致肥胖與代謝障礙之後續研究基礎，以利未來應用於臨床上解決其導致肥胖之副作用。
Olanzapine (olz) is a commonly used atypical antipsychotic drug, and it induces well known metabolic side effects, including weight gain and obesity. Rapamycin (rapa) is an immunosuppressant drug that can inhibit cell proliferation and block cell cycle. Previous studies have demonstrated that the inhibition effects of rapamycin on mammalian target of the rapamycin (mTOR) pathway can contribute to the decrease of body weight and the balancing of glucose level. C57BL/6JNarl mice were used in this study and randomly divided into four groups: control, olz, rapa and olz combined rapa treatment. The results showed that body weight gain was significantly increased in olz group compared to the control group. Interestingly, olz-induced weight gain was inhibited by rapa (p<0.05) on day 21~35. However, the hepatocellular vacuolation and abdominal adipose tissue sections showed no significant difference in each group. Western blotting results suggested that taking olz may increase stearoyl-CoA desaturase-1 (SCD1) protein expression in liver. Food consumption was higher in olz group and lower in rapa group. On the other hand, the serum leptin concentration was lower in olz group and higher in rapa group. Therefore, we speculated that the mTOR pathway inhibitor, rapa, could decrease food consumption and body weight gain due to its effect on elevating of serum leptin concentration. The results of this study provide evidences on olz-induced obesity, and may help in alleviating of olz-induced metabolic disorder.
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