Fenofibrate ameliorates insulin resistance in lipoprotein lipase heterozygous knockout mice and its possible mechanisms

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, and WT group. Mice in LPL+ /-(FB)group were gavaged with fenofibrate(50 mg·kg-1·d-1)for 8 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. (Chin J Endocrinol Metab, 2018, 34: 867-871) Key words: Lipoprotein lipase; Insulin resistance; Fenofibrate; Oxidative stress