Polydatin Alleviates High Fructose-induced Glycolipid Dysmetabolism By Activating AMPK Signaling Pathway

Aims:This study aims were to compare the alleviating effect of polydatin(POD)and resveratrol(RES)on glucose and lipid dysmetabolism induced by high fructose diet,and to reveal the mechanism of POD in preventing and treating glucolipid metabolism abnormalities.Methods:1.Based on the model of glucolipid metabolism disorder induced by high glucose diet in C57BL/6J mice,POD and RES were used for intervention.They were randomly divided into 4 groups: normal control group(Control),high glucose group(Model),polydatin group(50 mg/kg POD)and resveratrol group(50 mg/kg RES).The experiment lasted for 18 weeks.During the experiment,the body weight,water intake and food intake of mice were recorded,and fasting blood glucose(FBG)and insulin tolerance(ITT)were detected.Before the experiment is over,feces of mice were collected for the detection of intestinal microbes and short-chain fatty acids.At the end of the experiment,the blood and liver tissues of mice were collected for blood biochemical detection,histopathological detection,m RNA and protein detection.2.Based on C57BL/6J mice model of glucolipid metabolism disorder induced by high glucose diet,valeric acid or caproic acid alone group and POD combined group were used for intervention.The levels of FFA,TC and TG in serum and liver were detected at pharmacodynamic level,and the protein levels of AMPK signaling pathway and m RNA levels of short-chain fatty acid receptor were detected in mechanism level.3.The binding ability of POD,RES and AMPK was predicted through computer molecular simulation docking.The docking area was active pocket area of AMPK,which function was AMPK activation.Results:1.POD and RES have similar effects in alleviating glucose metabolism disorder,and both significantly improve insulin tolerance,serum insulin,glycosylated hemoglobin,insulin resistance index,and liver glycogen accumulation.POD was more effective than RES in improving lipid metabolism disorder,which POD significantly reduced serum FFA,TC,TG,LDL-C levels,liver FFA,TC and TG levels,while RES did not significantly improve lipid metabolism abnormalities.POD and RES significantly reduced MDA level and TXNIP protein level in liver,which increased SOD activity and activated AMPK signaling pathway.POD significantly upregulated the protein levels of p-AMPK-α(Thr172),CPT-1α,PPAR-α,PPAR-γ,p-ACC(Ser79),p-Akt(Ser473),p-PI3KP85(Tyr485)and p-IRS1(Ser307).RES significantly upregulated the protein levels of p-AMPK-α(Thr172),CPT-1α,PPAR-α,p-IRS1(Ser307),while RES did not significantly change the protein levels of PPAR-γ,p-ACC(Ser79),p-Akt(Ser473)and p-PI3KP85(Tyr485).POD and RES significantly increased the α-diversity of intestinal microflora.POD significantly increased the contents of valeric acid and caproic acid in feces,while RES had no significant effect on the contents of short-chain fatty acids in feces.2.Valeric acid significantly reduce the levels of TC and FFA in liver,while caproic acid significantly reduce the levels of TC,TG,FFA in serum and TG,FFA in liver.The combination of caproic acid or valeric acid and POD increased the effect of POD on reducing serum FFA,TC,LDL-C and liver FFA.Both caproic acid and valeric acid upregulated AMPK protein level,and POD combined with caproic acid/valeric acid upregulated P-ACC(Ser79)protein level.Meanwhile,neither caproic acid and valeric acid had no significant effect on m RNA levels of short-chain fatty acid receptors GPR41 and GPR43.3.The predicted binding score of POD was higher than that of RES(-8.677 vs-6.802)。Conclusions:1.Based on the model of glucolipid metabolism disorder induced by high-fructose diet in mice,the study shows that POD and RES have similar effects in alleviating glucose metabolism disorders,and POD has a better effect than RES in improving lipid metabolism disorders.Both POD and RES significantly reduced liver oxidative stress and activated the AMPK signaling pathway.The study proposed a potential mechanism by which POD is superior to RES in improving abnormal lipid metabolism,which may be that POD promotes the accumulation of caproic and valeric acids by regulating intestinal flora,thereby further promoting AMPK activation.2.Both valeric acid and caproic acid can improve abnormal lipid metabolism and activate AMPK,and can enhance the effect of POD on improving abnormal lipid metabolism in mice.