中文摘要：

小檗碱（BBR）具有多种药理活性。己有的研究表明BBR不仅可以通过拮抗HSP70-TNFα降低高热所引起的体温升高,还可以对抗低温所引起的体温降低。但是对于后者的分子机制尚不十分清楚。因此,我们以产热重要因子UCP1（uncoupling protein 1）为对象,对于BBR在低温条件下的作用机制进行了研究。本研究分别使用了野生型和Ucp1–/–基因敲除小鼠进行整体动物实验,使用原代脂肪细胞和HIB-1B细胞系进行体外实验。低温条件控制在4°C。结果表明,低温条件下小鼠体温明显下降,BBR可以明显的抑制这种体温的下降。同时小鼠棕色脂肪组织中Ucp1表达升高,BBR则进一步促进其表达。然而,Ucp1–/–基因敲除小鼠中BBR的抑制体温降低的作用消失,表明Ucp1基因是BBR防治低温时体温降低的主要靶点。进一步研究表明,Ucp1基因转录启动区上游转录响应元件NFE2（nuclear factor erythroid-derived 2）具有增强Ucp1基因表达的作用。BBR与NFE2的结合有温度依赖性。低温时,BBR与NFE2的亲和力明显增强,从而促进Ucp1基因的表达。本研究对于认识BBR通过作用于棕色脂肪进行产热、调节体温以及提高低温耐受性具有重要的意义。

英文摘要：

Berberine （BBR） has a variety of pharmacological activities. Studies have reported that BBR not only reduces heat stress-induced fever but also inhibits lower body temperatures due to cold stress. Heat stress can be reduced via BBR treatment, which antagonizes HSP70-TNFa to regulate the body temperature alteration. In cold stress, however, the molecular mechanism of BBR-induced inhibition of hypothermia remains unclear. Therefore, we studied whether BBR promoted uncoupling protein 1 （UCP1, a crucial protein of thermogenesis） expression and its mechanism under cold stress. Wild type mice and Ucpl-/- mice were used for the in vivo experiments, and primary brown adipocytes and brown adipocytes HIB-1B were used for the in vitro studies. The cold stress was set at 4℃. The results showed that at 4℃, the body temperature of mice was decreased. BBR effectively inhibited this hypothermia. Simultaneously, Ucpl expression in brown adipose tissue （BAT） cells was significantly increased, and BBR promoted Ucpl expression. However, in Ucpl-knockout mice, the effect of BBR on hypothermia disappeared during cold stress, indicating that the main target for BBR regulation of body temperature was Ucpl. Further studies showed that the transcriptional response element NFE2 （nuclear factor erythroid-derived 2） in the upstream of the Ucpl promoter region contributed to the positive regulatory role on Ucpl expression at lower temperature. BBR could bind to the sequence of NFE2 response element in a temperature-dependent manner. Increased affinity of BBR binding to NFE2 response element in cold stress significantly strengthened and enhanced the expression of Ucpl. This work was important for understanding the role of BBR on thermogenesis in BAT, body temperature regulation and temperature tolerance under cold conditions.