基于Dio2促产热效应研究UCP1诱导剂黄芩素的抗肥胖作用及分子机制

新近研究表明增加脂肪组织中产热基因解偶联蛋白1（UCP1）的药物有可能减少体内脂肪从而抵抗肥胖。然而，促进棕色脂肪活化和白色脂肪棕色化的药物研发始终未取得实质性进展。申请人在前期研究中采用CRISPR/Cas9基因编辑技术在棕色脂肪细胞构建UCP1诱导剂高通量筛选模型，筛选获得具有明显UCP1诱导作用的天然产物黄芩素，它可促进正常小鼠棕色脂肪产热和白色脂肪棕色化，显著抵抗高脂喂养小鼠诱发的肥胖，而碘甲腺原氨酸脱碘酶Ⅱ（Dio2）有可能是介导黄芩素促产热效应的关键靶点。目前黄芩素抗肥胖的具体机制尚不明确。本课题拟采用转基因ob/ob与高脂诱导肥胖动物及脂肪细胞模型，联合反向找靶、RNA Sequencing和脂质组学技术，明确UCP1诱导剂黄芩素的抗肥胖作用，并探究其通过Dio2促进棕色脂肪产热和白色脂肪棕色化抗肥胖的潜在机制。本研究将为抗肥胖药物研发提供新的思路，为肥胖症治疗带来希望。

Recent studies showed that the drug increasing thermogenic gene expression of UCP1 in adipose tissue might be the novel approach for the treatment of obesity through reducing body fat. However, no substantial progress has been made in the drug research and development for activating brown fat and promoting white fat browning yet. In the previous study, we established the high throughput screening model for UCP1 inducer in brown adipocytes utilizing CRISPR/Cas9 gene-editing technique and found natural product Baicalein with significant UCP1-inducing effect. Baicalein not only promoted the brown fat thermogenesis and white fat browning in normal mice, but significantly protected against high fat diet-induced obesity in mice. The mechanism investigation suggested that type II iodothyronine deiodinase (Dio2) might be the key target mediating thermogenic effect of Baicalein. To date, the anti-obesity underlying mechanism of Baicalein are not well understood. In the current study, we are going to use the high fat diet-induced obesity and transgenic ob/ob obesity animal models and adipocytes model, combined with target fishing, RNA sequencing and lipidomics techniques to confirm the anti-obesity effects of UCP1 inducer Baicalein and further investigate the underlying mechanism that Baicalein protected against obesity through promoting brown fat thermogenesis and white fat browning mediated by Dio2. The findings will provide the new idea for anti-obesity drug development and bring hope for the treatment of obesity.