The Mechanism For The Improvement Of Insulin Resistance In Obese Mice By Jaceosidin

Endoplasmic reticulum stress plays a crucial role in the development of obesity, insulin resistance and type â…¡ diabetes. Recently, more and more studies indicate that ER stress maintains on high levels in obese patients and obese mouse models. Despite that more and more studies concern ER stress, and the studies are more and more thorough, there are no efficient methods for the improvement of insulin resistance in obese patients through reducing ER stress. Of course, there are still no effective drugs for curing these patients. Our current study concerns the relationship of insulin resistance and ER stress in obese mice. After administration of jaceosidin, steatohepatitis and ER stress in obese mice are lightened, and insulin resistance is greatly improved.In the first chapter, we firstly established a mouse model of obesity, and measured and analyzed basal blood glucose, basal serum insulin, the ratio of fat pads around epididymis, fat cell volumes of fat pads around epididymis, glucose tolerance and insulin tolerance test in obese mice. Compared with lean control mice, the basal blood glucose, basal serum insulin, the ratio of fat pads around epididymis, fat cell volumes of fat pads around epididymis increased significantly in obese mice. Moreover, glucose tolerance and insulin sensitivity decreased significantly. These results imply that blood homeostasis was disturbed and insulin resistance was established in obese mice, and this model was ready for the following study. We intraperitoneally injected2mg/kg and4mg/kg jaceosidin, and injected4mg/kg pioglitazone as a positive control. After administration for two weeks, the ratio of fat pads around epididymis of body weight was slightly decreased, while fat cell volumes decreased significantly. We observed severe steatohepatitis in obese mice, and the content of triglyceride in the liver homogenates was significantly reduced by4mg/kg jaceosidin.4mg/kg jaceosidin significantly decreased serum levels of alanine transarninase (ALT) and aspartate aminotransferase (AST). Meanwhile,4mg/kg jaceosidin significantly decreased basal blood glucose, basal insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) in obese mice. Moreover,4mg/kg jaceosidin significantly increased blood glucose and insulin sensitivity in obese mice.In the second chapter, we investigated the effect of jaceosidin on ER stress in the liver of obese mice. Firstly, we found that steatohepatitis was obviously improved in obese mice, and mRNA levels of lipogenic genes including FASn, SCD1, ACC1and SREBP1c were significantly reduced by jaceosidin. Further study indicated that jaceosidin significantly increased mRNA levels of SERCA2b, and increased the mRNA levels of ER chaperones including HSPA5, PDIA3and DNAJB9in the liver of obese mice. Meanwhile, the protein levels of CHOP and phospho-eIF2a were significantly increased by4mg/kg jaceosidin. In the liver of obese mice, the mRNA levels of glucose-6-phosphatase (G6Pase) in obese mice were significantly higher than that in lean mice, and jaceosidin significantly reduced the mRNA levels of G6Pase, implying that jaceosidin significantly reduced the levels of free glucose in peripheral blood. As expected, jaceosidin increased sensitivity to insulin in insulin-resistant myotubes, and up-regulated the protein levels of SERCA2b, thus reducing ER stress in insulin-resistant myotubes.In all, our current study reports for the first time that jaceosidin increases the expression of SERCA2b, thus up-regulates the expression of ER chaperones, enhances ER folding capacity, lightens ER stress in obese mice, and improves glucose homeostasis in the end. In addition, we observe similar results in an in vitro insulin-resistant model, which implying that jaceosidin might be a candidate for curing insulin resistance. And further study for the mechanism of jaceosidin might make benefits for the therapy of type â…¡ diabetes.