高脂饲养大鼠脂代谢调控基因的表达与胰岛素抵抗的关系及机制

目的探讨高脂饲养SD大鼠脂代谢基因表达的改变与胰岛素抵抗（IR）的关系。方法8周龄雄性SD大鼠随机分为3组：正常饲养组（NC,10只）、高脂饲养组（HF,10只）、高脂饲养＋吡格列酮15mg·kg^-1·d^-1进行灌胃组（HP,12只）。饲养20周时测定血清、肝脏及肌肉组织中TG含量,3组均行正常血糖高胰岛素钳夹试验,并用实时定量PCR方法分析脂肪、肝脏和肌肉中脂代谢调控基因mRNA表达的变化。结果饲养20周时,与NC组比较,HF组血清TG增加45．0％（P〈0．01）,肝脏和肌肉TG含量增加2．28倍和9．31倍（P〈0．01）;HF组葡萄糖的输注率（GIR）下降61％（P〈0．01）,存在明显的IR;脂肪组织脂肪酸合成酶、激素敏感酯酶表达分别增高21．3％、28．2％（P〈0．05）;肝脏乙酰辅酶A羧化酶表达增高48．3％（P〈0．05）、肉毒碱脂酰转移酶1（CPT-1）表达呈增高趋势（P〉0．05）;肌肉乙酰辅酶A羧化酶表达增加101．1％、CPT-1表达减少71．0％（P〈0．01）。HP组与HF组比较,血TG、肝脏TG、肌肉TG分别下降66．0％、64．5％及59．6％,GIR增加1．54倍,脂代谢基因的表达也发生了明显的改变。结论高脂饲养可引起sD大鼠肝脏和肌肉组织脂肪异位沉积及IR,吡格列酮干预可以改善,可能与脂代谢调控基因的改变有关。

The mechanism of and relationship between lipid metabolism genes expression and insulin resistance in high fat-fed mice

OBJECTIVE: To observe the relationship between changes of genes expression related to lipid metabolism and insulin resistance induced by high fat diet in SD rats. METHODS: Normal 8-week old male SD rats were randomly divided into 3 groups. They were fed with normal chow (NC, n = 10), high fat diet (HF, n = 10) and high fat diet supplemented with pioglitazone 15 mg x kg(-1) x d(-1) (HP, n = 12). The TG content of liver and skeletal muscle of the rats was measured. Glucose infusion rate (GIR) was used to evaluate the insulin sensitivity by using euglycemic-hyperinsulinemic clamp method. Genes expression was investigated using real-time PCR method. RESULTS: After high fat feeding for 20 weeks, the serum TG, the content of TG in the liver and skeletal muscle of the rats in the HF group increased 0.45, 2.28 and 9.31 fold respectively as compared with those in the NC group. The change of TG content in the liver and skeletal muscle was associated with the reduction of GIR (6.16 +/- 0.75) mg x kg(-1) x min(-1) vs (15.82 +/- 2.10) mg x kg(-1).min(-1) (P < 0.01)]. As compared with the NC group, the expression of hormone-sensitive lipase (HSL) and fatty-acid synthase (FAS) gene in the HF group was enhanced by 28.2% and 21.3%, respectively (P < 0.05). In addition, the expression of acetyl-CoA carboxylase1 (ACC1) mRNA in the liver increased 48.3% (P < 0.05), increased 101.1% (P < 0.01) and carnitine palmitoyltransferase 1 (CPT-1) decreased 71.0% (P < 0.01) in the skeletal muscle in the rats of HF group. As compared with those in the HF group, GIR increased 1.54 fold in the HP group and on the contrary, serum TG, liver TG and muscle TG decreased about 66%, 64.5% and 59.6% respectively in the HP group (P < 0.05). Accordingly, the expression of FAS and HSL in the adipose tissue and the expression of ACC1 in the liver were reduced (P < 0.05) and the expression of CPT-1 was enhanced and ACC2 was reduced in the muscle (P < 0.01) in the HP group. CONCLUSIONS: The changing expression of genes related to lipid metabolism may play a role in the accumulation of lipids in non-adipose tissue and the induction of insulin resistance in rats fed with high fat diet.