Role Of Exenatide In Hepatic Gluconeogenesis Genes In The Diet-induced Obese Rats

Objective:1. To observe the effect of exenatide on hepatic glucose and lipid metabolism indiet-induced obese rats.2. To investigate the role of exenatide on hepatic gluconeogenesis genes indiet-induced obese rats.Methods:1. The male Sprague-Dawley rats were randomly distributed into two groups:standard diet (NC, n=8); high-fat diet (HF, n=15). After8weeks, the high-fat dietrats were distributed randomly into the following two groups: high-fat diet (HF, n=7)and exenatide,10ug/kg, twice a day (HF+Exe, n=8). Treatment was continued for8weeks.2. At the end of the experiment, the rats were fasted for12h. After oraladministration of glucose (2g/kg body weight), blood glucose levels were examined.We detected body and liver weight, and calculated liver index (liver weight/bodyweight%). We also detected serum insulin, glucose, total cholesterol, triglyceride,free fatty acid and calculated insulin resistance index（FBS×FINS/22.5）.3. Folth method was applied to measure the liver TG concentration. Histologicalchanges were obversed with haematoxylin and eosin (H&E), oil red O staining.4. Expressions of Forkhead box O1(FOXO1), phosphoenolpyruvatecarboxykinase (PEPCK), glucose-6-phosphatase (G6pase), insulin receptorsubstrate-2(IRS-2), glucose transporter-2(GLUT-2) genes were detected by real-timePCR.5. Expression of FOXO1protein level was measured by western blot. Results:1. Compared with NC group, high-fat diet significantly increased body weight,liver index, liver TG, plasma TG, FINS, HOMA-IR in HF rats (P<0.05); Comparedwith HF rats, exenatide administration significantly reduced body weight, liver index,liver TG, plasma TG,FINS, HOMA-IR and FFA(P<0.05).2. Histopathology: the hepatic steatosis in HF group was more severe than thatof the control group; compared with HF group, the hepatic steatosis was significantlylightened in HF+Exe group.3. Real-time PCR: compared with NC group, the expression of FOXO1, PEPCK,G6Pase mRNA were raised (P<0.01), the expression of IRS-2, GLUT-2mRNA werereduced (P<0.05); Exenatide treatment attenuated the expression of FOXO1, PEPCK,G6Pase (P<0.01) and potentiated the expression of IRS-2, GLUT-2genes (P<0.05).4. Western blot: compared with NC group, the FOXO1protein levels werehigher in HF group (P<0.01); Exenatide treatment attenuated the level of FOXO1protein level in HF+Exe group (P<0.01).Conclusions:1. Exenatide treatment could significantly decrease obese rats weight, improvehepatic glucose and lipid metabolism and insulin resistance; exenatide might beapplied to obesity and metabolic syndrome treatment.2. Exenatide treatment could inhibit hepatic gluconeogenesis gene expression，improve insulin signal pathway. It may be the direct or indirect action that exenatidetreatment could improve metabolism homeostasis.