摘要目的 探讨在环境和遗传因素共同诱导的胰岛素抵抗状态下组织成纤维细胞生长因子21(FGF-21)及其受体(FGFR)的变化.方法 雄性apoE~(-/-)小鼠,随机分为普通喂养组(NF组,n=20)和高脂喂养组(HF组,n=20),喂养16周.以3-[~3H]-葡萄糖为示踪剂的扩展胰岛素钳夹技术评价小鼠胰岛素敏感性和糖代谢变化.用实时荧光定量PCR法检测肝脏和脂肪组织FGF-21、FGFR1、FGFR2、FGFR3和FGFR4以及β-klotho mRNA表达,用Western印迹法测定血浆和组织FGF-21蛋白水平.结果 HF组小鼠空腹血糖、血浆胰岛素、甘油三酯、游离脂肪酸和胆固醇水平明显升高(均P<0.01).在钳夹稳态时,HF组血浆胰岛素水平明显高于NF组(P<0.01),HF组葡萄糖输注率(GIR)明显低于NF组(P<0.01).在钳夹结束时,HF组葡萄糖清除率(G_(Rd))明显低于NF组(P<0.01).钳夹稳态期,NF和HF组肝糖输出率(HGP)分别被抑制约70%和51%(均P<0.01).HF组肝和脂肪组织FGF-21和β-klotho mRNA水平均明显高于NF组(均P<0.01).HF组肝和脂肪组织FGFR1和FGFR3 mRNA的表达明显较NF组显著增高(P<0.01和P<0.05).FGFR4 mRNA水平在HF组肝组织中的表达明显高于NF组(P<0.05).HF组血浆FGF-21蛋白水平明显高于NF组(P<0.01),肝和脂肪组织FGF-21蛋白水平也显著升高(均P<0.05).结论 高脂喂养apoE~(-/-)小鼠FGF-21、β-Klotho及FGFR1和FGFR3水平显著升高,它们可能是FGF-21调节糖脂代谢的主要作用靶点.

abstractsObjective To investigate the effects of high-fat diet induced insulin resistance on fibroblast growth factor-21 (FGF-21) and its receptors expression in ApoE~(-/-) mice. Method Male ApoE~(-/-) mice were randomly divided into normal-chow group(NF,n=20)and high-fat fed group(HF,n=20) and fed for 16 weeks. The insulin sensitivity and glucose-lipid metabolism in awake mice were evaluated by hyperinsulinemic-euglycemic clamp technique combined with 3-[~3H]-glucose as a tracer. The Mrna expressions of FGF-21,β-klotho, and FGFR1-4 were measured by quantitative real-time PCR. FGF-21 protein levels were determined by Western blot. Results Fasting blood glucose, plasma insulin and free fatty acids, triglycerides, free fatty acids, and cholesterols were significantly elevated in HF group compared with NF group(all P<0.01). During the steady-state of clamp, plasma insulin was significantly higher in HF group than that in NF group(P<0.01), and glucose infusion rate was also significantly decreased(P<0.01). At the end of insulin clamp, glucose disappearance rate was significantly lower in HF group than that in NF groups(P<0.01). Hepatic glucose production in NF group was suppressed by 70% ,while in HF group it was suppressed by 51%. The FGF-21 Mrna expressions of hepatic and adipose tissues in HF group were significantly increased compared with NF group(both P<0.01), and β-klotho Mrna expressions increased(P<0. 05). In hepatic and adipose tissues, FGFRI, Mrna expressions were higher in HF group than those in NF group(both P<0.01) ,and FGFR3 Mrna increased(P<0.01 and P<0.05, respectively). In hepatic tissue,FGFR4 Mrna levels were significantly up-regulated in HF group(P<0. 05). Plasma FGF-21 levels were elevated in HF group compared with NF group(P<0.01) ,and FGF-21 protein expressions of hepatic and adipose tissues were also increased(both P<0.05). Conclusion FGF-21, β-klotho, FGFR1, and FGFR3 were significantly up-regulated in ApoE~(-/-) mice fed by high-fat diet, and they might be the targets in regulating glucose-lipid metabolism by FGF-21.