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奥氮平对小鼠白色脂肪米色化的抑制作用及其机制

Inhibition and mechanism of olanzapine on white adipose tissue beiging in mice

  • 摘要: 从奥氮平(olanzapine,OLA)对白色脂肪米色化(beiging)的调节作用探讨其引起代谢紊乱的可能机制。C57BL6/J小鼠连续28 d灌胃给予高、低剂量(4,8 mg/kg)OLA,隔天记录体重及摄食变化;通过糖耐量实验和冷应激考察小鼠血糖调控和产热能力的变化。分离小鼠肾周(pWAT)、附睾(eWAT)及腹股沟(iWAT)处白色脂肪,通过解偶联蛋白-1(UCP-1)免疫组化技术和苏木精-伊红染色确证米色化程度的改变;通过Western blot考察奥氮平对米色脂肪分化关键调控蛋白哺乳动物雷帕霉素靶蛋白(mTOR)活化和Notch1胞内结构域(N1ICD)表达的影响。实验结果表明:OLA可致小鼠基础产热明显降低,并可抑制环境适应性产热和葡萄糖利用。OLA引起腹股沟处米色脂肪分化异常,抑制冷应激诱导的白色脂肪米色化及UCP-1激活,并显著上调磷酸化mTOR(p-mTOR)与N1ICD的表达。以上结果提示,白色脂肪米色化的抑制作用参与到OLA诱导的代谢紊乱,mTOR-Notch信号通路的激活可能是其中的关键分子事件。

     

    Abstract: As one of the first-line antipsychotic drugs, olanzapine(OLA)inducing insulin resistance and metabolic disorder has become a serious clinical concern. This study aimed at investigating the effect of OLA on white adipose tissue(WAT)beiging as a potential mechanism behind its metabolism-disturbing effects. C57BL6/J mice were orally administered with low and high-dose OLA(4, 8 mg/kg, once daily)for 28 consecutive days; body weight and food intake were recorded every other day. Mice were subjected to glucose-tolerance test(GTT)and a cohort from each group was challenged with cold stress for 36 h before sacrifice. The perirenal, epididymal and inguinal WAT were carefully dissected, weighed and processed separately for hematoxylin-eosin staining, UCP-1 immunohistochemical and Western blot analysis. The results showed that OLA induced significant impairment in basal heat generation and glucose regulation. There were fewer beige adipocytes in the inguinal WAT after OLA treatment. The beiging of inguinal WAT in response to cold stress was significantly inhibited in OLA-treated mice. Mechanistically, OLA induced the activation of mTOR-Notch pathway, as evidenced by a significant increase in phosphorylated mammalian target of rapamycin(p-mTOR)and intracellular domain of Notch1(N1ICD)expression. Together, our study reveals that the inhibitory effects on WAT beiging may explain the propensity of OLA to induce metabolic disturbance, and mTOR-Notch pathway activation could play key roles in this effect. Future validation and elucidation of these novel findings are expected to provide novel insights into the metabolic risks of OLA and related second generation antipsychotics, which may lead to innovative intervention strategies in the clinic.

     

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