利拉鲁肽诱导肥胖2型糖尿病大鼠白色脂肪组织中FGF21的表达及机制

Research of mechanisms of liraglutide inducing expression of fibroblast growth factor 21 in white adipose tissues of obese type 2 diabetic rats

目的 探讨利拉鲁肽(liraglutide,LRG)对肥胖2型糖尿病大鼠白色脂肪组织(white adipose tissue,WAT)中成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)表达的影响及机制。方法 ♂SD大鼠,随机分为对照组、2型糖尿病组(DM)及2型糖尿病+利拉鲁肽组(DM+LRG),后两组先给予高脂饮食,然后腹腔注射30 mg·kg^(-1)链脲佐菌素构建肥胖2型糖尿病模型,DM+LRG组再腹腔注射利拉鲁肽0.4 mg·kg^(-1)·d^(-1),每天2次,干预6周。检测血液生化指标以及FGF21水平,HE染色检测附睾脂肪组织的形态学变化,免疫组化、RT-PCR和免疫印迹法检测WAT中FGF21、PPARγ、FGFR3、β-Klotho、LKB1、AMPK、ACC的mRNA、蛋白表达与磷酸化及MAPK信号分子的磷酸化水平。结果 DM组大鼠体重和血脂、ALT、AST增高,FGF21降低,附睾脂肪细胞体积增大,FGF21、PPARγ、p-FGFR3、β-Klotho、p-LKB1、p-AMPK、p-ACC的表达降低,p-ERK、p-JNK、p-p38的表达均升高;DM+LRG组上述各指标均逆转。结论 利拉鲁肽具有明显的降脂作用,其机制可能与增加脂肪组织中FGF21的表达,进而激活AMPK信号通路和抑制MAPK通路有关。

Aim To investigate the effect of liraglutide on expression of fibroblast growth factor 21 in white adipose tissues and its mechanisms. Methods Male SD rats were subjected to a standard control diet or high-fat diet（HFD） for 12 weeks,then the HFD group was injected introperitoneally with 30 mg·kg（-1） streptozotocin to induce type 2 diabetes mellitus model. Half number of rats of type 2 diabetes mellitus were injected with liraglutide（DM ＋ LRG,0.4 mg· kg（-1）·d（-1）,two times one day） for another 6 weeks. Serum biochemical indices and FGF21 levels were detected. The pathological changes in epididymal adipose tissues were detected by HE staining. The mRNA and protein expression and phosphorylation of FGF21, peroxisome proliferator-activated receptor γ（PPARγ）,fibroblast growth factor receptor 3（FGFR3）,β-Klotho,liver kinase B1（LKB1）,AMP-activated kinase（AMPK）,acetyl-Co A carboxylase（ACC） and phosphorylation of signaling molecules in MAPK pathway were assessed by RT-PCR,immunohistochemistry and Western blot respectively. Results Body mass and serum lipid,ALT and AST levels increased in DM group,while FGF21 level decreased,and the volume of adipose cells in epididymal adipose tissues was expanded. Expressions of FGF21,PPARγ,p-FGFR3,β-Klotho,p-LKB1,pAMPK,p-ACC were down-regulated,while p-ERK,p-JNK and p-p38 expression were all increased. These indices were reverted by liraglutide treatment. Conclusion Liraglutide has significant lipid-lowering effect,which maybe related with increased FGF21 expression,activating AMPK pathway and inhibiting MAPK pathway.