Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity
Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity
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DOI：
10.1074/jbc.275.22.16638
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发表时间：
2000-06-02
影响因子：
4.8
通讯作者：
Staels, B
中科院分区：
文献类型：
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作者：
Guerre-Millo, M;Gervois, P;Staels, B
贝特类和格列酮是目前分别用于治疗血脂异常和胰岛素抵抗(IR)的两类药物。格列酮是胰岛素增敏剂，通过激活过氧化物酶体增殖物激活受体(PPAR)γ亚型发挥作用，而贝特类药物则通过PPARα发挥降脂活性。为了确定PPARα激动剂是否也改善胰岛素敏感性，我们测量了三种PPARα选择性激动剂非诺贝特、环丙贝特和新化合物GW9578在两种高脂饮食诱导的(C57BL/6小鼠)或遗传性(肥胖的Zucker大鼠)IR啮齿动物模型中的能力。在产生选择性激活PPARα的血清浓度的剂量下，这些化合物显著降低了两种动物模型的高胰岛素血症和高血糖。这一效应依赖于胰岛素对葡萄糖利用作用的改善，环丙贝特治疗的IR肥胖Zucker大鼠对腹腔内葡萄糖的反应降低了胰岛素峰值。此外，非诺贝特治疗防止了高脂饮食导致的体重和脂肪组织质量增加，而不影响卡路里摄入量。体内PPARα激活的特异性表现为PPARα靶基因表达的显著变化，而PPARγ靶基因的mRNA水平在处理动物中没有变化。这些结果表明，在胰岛素抵抗的动物模型中，具有选择性PPARα激活谱的化合物可以降低胰岛素抵抗，而不会对体重和脂肪组织质量产生不利影响。
Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPAR alpha. To determine whether PPAR alpha activators also improve insulin sensitivity, we measured the capacity of three PPAR alpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPAR alpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPAR alpha activation in vivo was demonstrated by marked alterations in the expression of PPAR alpha target genes, whereas PPAR gamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPAR alpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.