大黄酸激活SIRT1信号通路对脂肪组织重塑和稳态平衡的作用及机制研究

A growing body evidence indicates adipose tissue undergoes a continuous process of remodeling that is pathologically accelerated in the obese state. Therefore a lot of studies are focused on the exploring the role of Chinese traditional medicines in the adipose tissue remodeling and homeostasis. SIRT1, one kind of longevity gene, is a key regulator in adipose tissue. So SIRT1 activators, such as resveratrol, has been used for treatment of obesity. Rhein, a natural compound from Rheum palmatum L, has been found to protect obesity and related metabolic disorders. However, the exact mechanism of rhein action has not been explored. In this project, we plan to use adipocyte specific SIRT1 knock out mice as animal model and want to invest effect of rhein on adipose browning, aberrant production of adipokines, infiltration and polarization of macrophage and unhealthy pathological expansion in adipose tissue in vivo and vitro. Further we will uncover the signaling pathway of rhein in activating SIRT1. This finding will contribute to explore the molecular mechanism of rhein in obesity and will provide scientific evidence of Chinese traditional medicine for treatment and prevention of obesity and related diseases by targeting SIRT1 signaling pathway.

肥胖的本质在于脂肪稳态失衡和病理性重构，调控脂肪重塑的药物成为肥胖及代谢综合征研究领域的热点。SIRT1作为能量代谢开关，是调控脂肪功能的关键，本课题组长期致力于SIRT1信号通路研究，并在前期探索中发现大黄酸抗肥胖及改善代谢的确切作用，据此提出科学假说：大黄酸激活脂肪局部SIRT1信号通路，通过诱导脂肪组织棕色化，调节脂肪因子分泌，抑制巨噬细胞浸润及极化改变，减轻病理性扩充，从而调控脂肪组织重塑，维持稳态平衡。为此，本项目组在已成功构建脂肪特异性SIRT1基因敲除小鼠基础上，采用动物能量代谢检测系统、细胞代谢动态分析及体外组织培养等方法开展相关实验证实以上假说，揭示大黄酸抗肥胖作用的分子靶点和信号通路。在此基础上进一步阐释大黄酸激活SIRT1的上游信号通路，为深入研究大黄酸在全身能量代谢调控中的作用和机制奠定理论基础，从而为肥胖及代谢综合征的防治提供新的思路和方法。

SIRT1作为长寿基因，是调控脂肪功能的关键开关。寻找SIRT1的激活剂是目前抗肥胖和衰老的一个重要研究领域。本项目通过基因工程小鼠，动物能量代谢检测系统（CLAMS）、小鼠MRI成像、免疫组化、Westernblot、体内外研究等方法明确大黄酸改善肥胖引起的代谢紊乱和脂肪组织病理性重构的关键机制在于激活脂肪组织SIRT1的表达。同时，我们重点研究了大黄酸对棕色脂肪组织的调控作用，证实大黄酸主要通过激活SIRT1，促进肩胛骨棕色脂肪组织UCP1表达，增加机体能量消耗，从而改善肥胖引起的代谢异常。在此基础上，我们探讨大黄酸调控脂肪组织SIRT1表达的上游信号通路，发现大黄酸激活SIRT1的分子机制可能与促进棕色脂肪细胞JNK的磷酸化水平有关。以上研究为大黄酸在肥胖治疗中的进一步应用提供药理学依据，并为拓宽中药治疗肥胖及代谢综合征提供新的研究思路。