Erk1/2失活对FGF21调节糖脂代谢调控的影响

目的:探索细胞外信号调节激酶1/2(Erk1/2)失活对成纤维细胞生长因子21(FGF21)调节机体血糖平稳及改善异常血脂的影响。方法:选取8~10周龄雄性db/db小鼠,给予Erk1/2激酶抑制剂U0126(抑制Erk1/2磷酸化,使之失活)处理1周后,再分别给予重组人FGF21蛋白和腺病毒携带的FGF21(Ad-FGF21)处理,观察120 min内及4周后小鼠血糖、血脂及其相关调控基因的变化;同时,从体外细胞培养方面探索其分子机制。结果:给予db/db小鼠重组人FGF21蛋白处理120 min能显著下调血糖和甘油三酯水平,但这与U0126处理与否无关。给予Ad-FGF21处理4周能显著改善db/db小鼠异常血糖水平及葡萄糖和胰岛素耐受能力,降低机体脂肪含量,并改善异常血清甘油三酯水平,然而,这些变化仍与U0126处理与否无关。此外,在细胞信号转导的分子机制方面,Ad-FGF21处理能显著上调皮下脂肪组织Erk1/2磷酸化活性及过氧化物酶体增殖物激活受体γ(PPARγ)的表达水平,同时上调机体脂联素(adiponectin)mRNA及蛋白的表达水平(P0.05),但与U0126处理与否无关。在体外实验方面,FGF21处理能显著激活Erk1/2磷酸化,并上调PPARγ和adiponectin的表达水平;然而,给予U0126处理并不能抑制PPARγ和adiponectin的表达。结论:FGF21具有调节机体血糖平稳及改善异常血脂的生物学功能,但Erk1/2失活可能不影响FGF21调节血糖血脂的功能。

Pharmaceutical inactivation of Erk1/2 does not affect function of FGF21 to regulate glucose and lipid metabolic hemostasis

AIM: To investigate whether inactivation of extracellular signal-regulated kinase 1/2 (Erk1/2) will affect the function of fibroblast growth factor 21 (FGF21) to regulate glucose and lipid metabolism. METHODS: Male db/db mice (8 weeks old) were treated with U0126 (an inhibitor of Erk1/2 kinase) for 1 week, and then treated with recombinant human FGF21 protein and adenovirus-mediated FGF21 (Ad-FGF21). The profile changes of blood glucose and blood lipid were evaluated at 120 min or 4 weeks after FGF21 administration. Meanwhile, the molecular mechanism was explored by in vitro study. RESULTS: Treatment of db/db mice with recombinant human FGF21 protein significantly reduced blood glucose and triglyceride levels at 120 min after FGF21 administration, but these changes were comparable in U0126-treated mice. Furthermore, abnormal glucose and triglyceride levels, and glucose and insulin tolerance were strongly improved in db/db mice as accompanied with decreasing body fat content after 4 weeks of ad-FGF21 administration. Interestingly, treatment with or without U0126 did not influence these effects of FGF21. Mechanically, treatment with Ad-FGF21 significantly upregulated the protein levels of p-Erk1/2 and peroxisome proliferator-activated receptor γ (PPARγ) as well as the expression of adiponectin at mRNA and protein levels in adipose tissues. However, treatment with or without U0126 did not change the profiles. On the other hand, in vitro experiments also indicated that treatment of adipocytes with recombinant human FGF21 protein significantly activated Erk1/2 phosphorylation, and upregulated the expression levels of PPARγ and adiponectin (P<0.05). However, pre-administration of U0126 did not affect the profiles. CONCLUSION: Pharmaceutical inactivation of Erk1/2 by U0216 does not affect the biological function of FGF21 to regulate blood glucose balance and improve abnormal blood lipids in vivo.