The Mechanism Of Liraglutide Interfered In The Gloucose-Lipid Metabolic Disorder In Hypoadiponectinemia ApoE-/- Mice

Objective: To establish an insulin resistance (IR) animal model induced by hypoadiponectinemia in ApoE-/- mice and further to investigate the effects of hypoadiponectinemia on the related genes expressions of glucose-lipid metabolism and to examine the effects of liraglutide on the adiponectin gene inhibition-mediated insulin resistance.Methods: Thirty two ApoE-/- mice fed HFD for 16 weeks were subdivided into four groups. One group was given only high-fat diet (HF, n=6). The second group was given adenoviral control vectors (pAd-U6-GFP, GF, n= 8). The third group received adiponectin RNAi adenovirus (pAd-U6-Acrp30, ADI, n= 9) and the fourth group was given pAd-U6-Acrp30 and liraglutide (HEA, n=9). All adenoviral injections were given by the tail vein at the end of 14th and 15th weeks of HFD feeding. The HEA group was given intraperitoneally liraglutide (1mg/kg) once daily for 8 weeks from the 9 weeks. The gloucose-lipid metabolism basic biochemical indicators and insulin level in plasma were determined by enzymes or immunization methods. The level of plasma adiponectin was measured by ELISA. The mRNA expressions and protein levels of glucose-lipid metabolism related genes were measured by quantitative real time PCR and Dot-blot.Results: Free fatty acids (FFA), TC, TG, fasting plasma insulins (PIns) and LDL-C in adiponectin shRNA adenovirus injection group (ADI group) were significantly higher than those in two control groups (HF group and GF group, P<0.05) and Liraglutide-adiponectin shRNA adenovirus co-injection group (HEA group, P<0.01). Body weight and Fasting blood glucose (FBG) in HEA mice were significantly lower than control groups and ADI group (P<0.05), while HDL-C was significantly higher than ADI group (P<0.05). The mRNA expressions of PPARα,INSIG-2 and LDLr in ADI group were significantly down-regulated compared with two control groups and HEA group (P<0.01 and P<0.05), while HMGCR and SREBP-2 in HEA group were significantly up-regulated (P<0.01 and P<0.05). The GLUT-1 mRNA expression of hepatic tissues in ADI group was significantly decreased compared with two control groups and HEA group (P<0.01), in contrast, the PEPCK mRNA expression was significantly increased (P<0.05). The mRNA levels of HSL and PPARγin adipose tissues were significantly lower than two control groups and HEA group (P<0.01), and the FAS mRNA levels in adipose tissues were increased (P<0.01). In adipose tissues, ACC mRNA expression was lower in HEA group than ADI group (P<0.01). SCD-1 mRNA levels were reduced in ADI group compared with two control groups and HEA group (P<0.01). The adiponectin and Visfatin mRNA expressions of adipose tissues in ADI group were significantly decreased compared with two control groups (P<0.05 and P<0.01), and adiponectin expression level in HEA was significantly increased compared with ADI group (P<0.05). The visfatin of plasma and adipose tissues levels and plasma adiponectin level in ADI group were significantly decreased compared with two control groups and HEA group (P<0.01).Conclusion: Adiponectin gene inhibition can significantly aggratate glucose-lipid metabolic disorder in ApoE-/- mice with high-fat diet. Liraglutide administration can change the expressions of related genes of glucose-lipid metabolism and improve insulin resistance in ApoE-/- mice with RNAi-mediated adiponectin gene inhibition.