Fenofibrate ameliorates insulin resistance in lipoprotein lipase heterozygous knockout mice and its possible mechanisms / 中华内分泌代谢杂志

ABSTRACT

Objective To investigate the effect of fenofibrate on glucolipid metabolism and insulin sensitivity in lipoprotein lipase heterozygous knockout ( LPL+/-) mice, and to explore its mechanism. Methods LPL+/- mice and wild type ( WT) C57 mice were selected and divided into 3 groups ( n=6 each group)LPL+/-( FB) group, LPL+/-(W)group,andWTgroup.MiceinLPL+/-(FB)groupweregavagedwithfenofibrate(50mg·kg-1·d-1)for8 weeks. Mice in LPL+/-( W) and WT groups were orally fed with the same volume water as that in LPL+/-( FB) group for 8 weeks. Body weight was observed. Plasma triglyceride ( TG ) and free fatty acid ( FFA ) were measured. Intraperitoneal glucose tolerance test in 3 groups of mice were performed. The glucose area under the curve ( AUCG) and homeostasis model assessment for insulin resistance index ( HOMA-IR) were calculated. Insulin-stimulated Ser473 Akt phosphorylation in liver and skeletal muscle was measured by Western blot. Reactive oxygen species ( ROS) levels in liver and skeletal muscle were determined by dihydroethidium staining method and superoxide dismutase ( SOD) and catalase ( CAT) mRNA expression levels were detected by real-time PCR. Results Compared with LPL+/-( W) mice, body weight of LPL+/-( FB) mice was lowered, plasma TG and FFA levels were decreased by about 46.0％and 76.5％respectively, and fasting insulin level and HOMA-IR were decreased while there were no significant differences in fasting glucose level and AUCG between two groups. Insulin-stimulated Ser473 Akt phosphorylation levels in liver and skeletal muscle of LPL+/-mice were enhanced by fenofibrate. ROS level in skeletal muscle of LPL+/-( FB) mice was lower than that in LPL+/-( W) mice while there was no significant difference in ROS of liver between two groups. Fenofibrate significantly increased SOD and CAT mRNA expressions in skeletal muscle of LPL+/-mice, but not in liver. Conclusion Fenofibrate reduces body weight, ameliorates lipid metabolism, and improves insulin sensitivity in LPL+/- mice, with reduced oxidative stress.