Study On The Mechanism Of COST Particles Inhibiting The Endoplasmic Reticulum Stress Regulating JAK2/STAT3 Signaling Pathway To Improve Leptin Resistance

Along with the diet and lifestyle changes,for example,often overeating,often stay up late,the occurrence of obesity is raising annually.Unreasonable diet,lacking of physical exercise,intaking too much fat and genetic factors are important factors leading to obesity.There is no safe medicine can be used for treating obesity.Many weight-loss drugs were removed from the market or be restricted because its mechanism is unknown or clear mechanism but can bring serious adverse reaction.So looking for new weight loss mechanism that non-toxic and effective has become an urgent need for development of new anti-obesity medicine.COST with good biological activity,especially the activity of lose weight is the average molecular weight less than 1000 dalton of chitosan oligosaccharide particles.COST is soluble in water and with good bioavailability.The previous research results show that COST has good activity to lose weight on obese sprague dawley rats,reducing weight effect of high dose COST is consistent with orlistat,mechanism research found that COST can significantly reduce the serum leptin level in sprague dawley rats and decrease the expression of leptin mRNA in adipose tissue.Study on weight loss activity and weight loss mechanism of COST through C57BL/6J induced by high fat diet and ob/ob.The results showed that COST had no effect on appetite,and had no weight loss activity on the ob/ob,but had good weight loss activity in C57BL/6J,reducing weight effect of high dose COST was consistent with orlistat.Preliminary results suggested that weight loss activity of COST is dependent on leptin.COST can significantly reduce the serum T-CHO,LDL-C content and significantly increase HDL-C content in ob/ob.At the same time,COST also can significantly reduce the serum content of T-CHO,TG,LDL-C and significantly increased the content of HDL-C in C57BL/6J,these results indicated that COST has the function of reducing blood lipid.In addition,COST can significantly reduce the content of serum glucose in ob/ob and C57BL/6J,that shows COST has hypoglycemic function.This study also showed that COST can significantly improve fatty liver disease,significantly reduce the accumulation of fat droplets in the liver and significantly reduce serum ALT,AST content in ob/ob.It is suggested COST has hepatoprotective effect.COST used alone can significantly reduce the serum content of leptin in C57BL/6J,indicated that COST improved leptin resistance in C57BL/6J obesity mouse.At the same time,COST can obviously improve inflammation,reduce myocardial cell inflammation in ob/ob,also find that COST can promote the formation of immune cells in the spleen of ob/ob,suggested that COST may have effects of anti-inflammatory and improving immunity.COST is safe and non-toxic,we found it had no toxic effect on kidney,heart,spleen and liver.COST significantly increased the protein expression of JAK2,STAT3,p-STAT3 in ob/ob liver.Each dose COST significantly increased JAK2,STAT3 protein expression in the hypothalamus of C57BL/6J.It is more important when using AG490 to block JAK2/STAT3 pathway by inhibiting JAK2 activity,after treated with COST,protein expression of JAK2,STAT3 increased significantly.High dose and middle dose of COST significantly increased JAK2,STAT3 protein expression,resistanced to AG490 inhibiting JAK2/STAT3 signaling transduction pathway in C57BL/6J liver.These results indicated that COST can promote leptin pathway JAK2/STAT3 signaling transduction.It is also found that COST had no effect on the expression of PTP1 B protein in the hypothalamus and liver both ob/ob and C57BL/6J,suggested that COST is not through reducing the expression of PTP1 B that inhibiting the activation of JAK2 to play anti-obesity activity.COST significantly reduced the expression of GRP78 protein,CHOPmRNA also significantly increased the expression of ATF6 mRNA in the liver and hypothalamus of the ob/ob.These results indicated that COST can alleviate the occurrence of endoplasmic reticulum stress in the liver and hypothalamus of ob/ob.In a word,COST has good slimming function,it is safe and non-toxic.At the same time that COST has a good hypolipidemic,hypoglycemic and hepatoprotective function.Research on the mechanism of COST anti-obesity activity showed that weight loss has a dependency on leptin.It is proved that COST promote leptin signal JAK2/STAT3 transduction,also proved that COST is not inhibiting the activity of PTP1 B to play a slimming effect.Further studies show that COST can reduce the occurrence of ERS.The mechanism that COST play a slimming activity may be in the promotion of the JAK2/STAT3 pathway and to mitigate the occurrence of ERS so as to improve the leptin resistance to achieve the purpose of weight loss.