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

摘要

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 ad-ipose 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 in-jected introperitoneally with 30 mg · kg-1 streptozoto-cin 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 bio-chemical indices and FGF21 levels were detected. The pathological changes in epididymal adipose tissues were detected by HE staining. The mRNA and protein ex-pression and phosphorylation of FGF21 , peroxisome proliferator-activated receptor γ ( PPARγ) , fibroblast growth factor receptor 3 (FGFR3),β-Klotho, liver ki-nase B1(LKB1), AMP-activated kinase (AMPK), a-cetyl-CoA carboxylase ( ACC ) and phosphorylation of signaling molecules in MAPK pathway were assessed by RT-PCR, immunohistochemistry and Western blot re-spectively. 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 ep-ididymal adipose tissues was expanded. Expressions of FGF21, PPARγ, p-FGFR3, β-Klotho, p-LKB1, p-AMPK, p-ACC were down-regulated, while p-ERK, p-JNK and p-p38 expression were all increased. These indices were reverted by liraglutide treatment. Conclu-sion Liraglutide has significant lipid-lowering effect, which maybe related with increased FGF21 expression, activating AMPK pathway and inhibiting MAPK path-way.