番石榴叶提取物通过AMPK-PGC-1α-FNDC5信号通路调节脂肪组织SVF细胞分化作用机制研究

Guava Leaf (GL), as a widely used herbal medicine in tropical and subtropical countries, has been introduced to treat diabetes for many years. In our previous study, We find that GL extracts improve the glucose metabolism and decrease the body weight significantly in SHRSP/ZF rats.Further studies showed that GL extract could increase the the protein expression of phosphorylation/total AMPK in skeletal muscle to influence the IRS-PI3K-AKT signaling pathway resulting in the GLUT4 transduction These results demonstrated that GL extracts exhibit a novel anti-diabetic effects by ameliorating glucose metabolism with increasing muscle fatty acid oxidation and improving insulin sensitivity. PGC-1α is a key cytokines in the downstream signaling pathway of AMPK. AMPK could upregulate the expression of PGC-1α，in turn, upregulate the expression of downstream FNDC5, which is C-terminally cleaved and secreted as irisin. Irisin could binding to an unknown receptor on the surface of adipocytes in white adipose tissue (WAT) resulting in the increase of UCP1 (highly expressed in brown adipose tissue and a marker of browning) The browning of WAT is associated with augmented mitochondrial density and oxygen consumption.Browning is accompanied by an increase in the energy expenditureand and the decrease of body weight. We speculate that GL may increase the expression of AMPK-PGC-1α-FNDC5 pathway to infulence the browning of WAT.Therefore, this project is focused on whether GL could improve the expression of AMPK-PGC-1α-FNDC5 signaling pathway and reinforce the browning of white adipose tissue by in vivo and in vitro experiment. Our findings will provide insight into clinical treatment for obesity and diabetes.

番石榴叶是民间常用的降糖中药，前期研究中，我们发现番石榴叶提取物可以显著降低SHRSP.ZF大鼠体重,改善糖耐量。进一步研究发现，番石榴叶提取物通过增加SHRSP. ZF大鼠骨骼肌AMPK，使GLUT4向细胞膜转运，从而降低血糖。PGC-1α是联系AMPK与GLUT4的重要中间环节，我们推测，PGC-1α很可能受AMPK刺激而被激活，使下游FNDC5表达增强，促使由骨骼肌来源的FNDC5诱导白色脂肪向棕色脂肪分化和脂肪燃烧，最终导致体重下降。本课题首次以2型糖尿病db/db小鼠和原代培养成肌细胞、脂肪组织SVF细胞为模型，通过细胞阻滞剂的应用，多角度探讨成肌细胞AMPK-PGC-1α-FNDC5信号通路和脂肪SVF细胞在番石榴叶提取物干预下的相互作用关系，以及脂肪SVF细胞由白色脂肪细胞向棕色脂肪细胞分化的作用靶点，这些结果将为番石榴叶提取物在治疗2型糖尿病和肥胖的临床应用中提供实验依据。

番石榴叶是民间常用的降糖中药，前期研究中，我们发现番石榴叶提取物可以显著降低SHRSP.ZF大鼠体重,改善糖耐量。进一步研究发现，番石榴叶提取物通过增加SHRSP. ZF大鼠骨骼肌AMPK，使GLUT4向细胞膜转运，从而降低血糖。PGC-1α是联系AMPK与GLUT4的重要中间环节，我们推测，PGC-1α很可能受AMPK刺激而被激活，使下游FNDC5表达增强，促使由骨骼肌来源的FNDC5诱导白色脂肪向棕色脂肪分化和脂肪燃烧，最终导致体重下降。本课题首次以2型糖尿病db/db小鼠和原代培养成肌细胞、脂肪组织SVF细胞为模型，通过细胞阻滞剂的应用，多角度探讨成肌细胞AMPK-PGC-1α-FNDC5信号通路和脂肪SVF细胞在番石榴叶提取物干预下的相互作用关系，以及脂肪SVF细胞由白色脂肪细胞向棕色脂肪细胞分化的作用靶点，这些结果将为番石榴叶提取物在治疗肥胖和2型糖尿病的临床应用中提供理论依据。