小檗碱促进白色脂肪米色化的药理活性评价及作用机制研究

Obesity is incurred because of the energy intake exceeds energy expenditure.Increasing evidence shows that promote beige remodeling of white fat, increase energy expenditure is an effective way to loss weight. In recent years , we have carried out to a lot of research work and mechanism study of berberine improving glucose and lipid disorder，and get some good results.Colleagues's study suggests that berberine could promote energy metabolism. Our preliminary results indicate that berberine can reduce the body weight and fat of high-fat diet -induced obese mice，moderate elevated body temperature and improve the overall energy expenditure.Research on cellular level shows that berberine can promote fat precursor cells differenciated into beige fat cells, this process is accompanied by the activation of AMPK. We hypothesized that AMPK signaling pathway is involved in the beige switching effect of white adipose tissue of berberine. This project intends to carry out a comprehensive evaluation of pharmacological activity of berberine,including promote fat remodeling, improve the body energy metabolism, and combined with the use of modern methods of molecular biology and cell biology to clarify the role of AMPK in this process. This project has important scientific significance for us to further elucidate the mechanism of natural product berberine in improving of obesity and glucose and lipid disorders.

肥胖是由于能量摄入超过能量消耗所产生的，越来越多的证据表明通过促进脂肪米色化、增加机体的能量消耗是一种有效的减轻体重的治疗方式。近年来，我们对小檗碱在改善糖脂代谢紊乱及作用机制研究方面进行了大量的研究工作，并取得了一些成果。我们前期研究结果表明小檗碱能够减轻高脂饮食诱导肥胖小鼠的体重、体脂、温和升高体温、提高整体能量消耗；细胞水平研究表明小檗碱能够促进脂肪前体细胞的米色化，此过程伴随着AMPK的激活，因此我们推测AMPK信号通路可能参与小檗碱促进脂肪米色化的作用过程。本课题拟开展全面评价小檗碱促进脂肪米色化、提高机体能量代谢的药理活性，并将结合运用现代分子生物学和细胞生物学研究方法，阐明AMPK在其中所发挥的作用。这对于我们进一步阐明天然产物小檗碱改善肥胖及糖脂代谢紊的作用机理具有重要的科学意义。

肥胖是以由于能量摄入超过能量消耗所产生的脂肪过剩为特征的疾病。越来越多的证据表明通过促进棕色/米色脂肪含量或活性以增加机体的能量消耗是一种有效的减轻体重的治疗方式。近年来，我们对小檗碱在改善糖脂代谢紊乱及作用机制研究方面进行了大量的研究工作并取得了一些的成果；同行研究提示在体内动物水平小檗碱具有促进能量代谢和降低体重的作用。本课题在动物水平全面考察了小檗碱在饮食肥胖小鼠模型和正常饮食小鼠的能量代谢的影响，重点考察小檗碱对棕色脂肪分化和白色脂肪米色化的作用并探究其作用机制。本项目研究发现小檗碱在细胞和动物水平特异性促进棕色脂肪分化，对白色脂肪米色化过程无明显作用；增加DIO小鼠和正常饮食小鼠中棕色脂肪含量和活性并提高能量消耗，抵抗肥胖并改善糖脂代谢。在机制上，研究表明小檗碱通过上调PRDM16转录活性及PRDM16/MED1复合物在棕色脂肪标志基因上的富集程度来促进棕色脂肪分化过程；这一过程不依赖于AMPK信号通路的激活。总的来说，我们初步阐明了小檗碱通过PRDM16通路特异性促进棕色脂肪分化过程，进而促进能量消耗并抵抗肥胖改善糖脂代谢。