Ye J M, Doyle P J, Iglesias M A, Watson D G, Cooney G J, Kraegen E W
Garvan Institute of Medical Research, Sydney, Australia.
Diabetes. 2001 Feb;50(2):411-7. doi: 10.2337/diabetes.50.2.411.
Peroxisome proliferator-activated receptor (PPAR)-alpha agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-gamma activation. Three-week high fat-fed male Wistar rats were untreated or treated with the specific PPAR-alpha agonist WY14643 or the PPAR-gamma agonist pioglitazone (both 3 mg x kg(-1) x day(-1)) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced whole-body insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulin-mediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-alpha and PPAR-gamma activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation.
过氧化物酶体增殖物激活受体（PPAR）-α激动剂可降低循环脂质水平，但对肌肉脂质代谢和胰岛素敏感性的影响尚不清楚。我们研究了PPAR-α激活是否能改善胰岛素抵抗大鼠的胰岛素敏感性，并将其与PPAR-γ激活的效果进行比较。对高脂喂养3周的雄性Wistar大鼠，在高脂喂养的最后2周不进行处理，或用特异性PPAR-α激动剂WY14643或PPAR-γ激动剂吡格列酮（均为3 mg·kg⁻¹·d⁻¹）进行处理。与吡格列酮一样，WY14643可降低基础血浆葡萄糖、甘油三酯（与未处理组相比降低16%）和瘦素（降低52%）水平，还可降低肌肉甘油三酯（降低34%）和总长链酰基辅酶A（LCACoA）（降低41%）（P<0.05）。与吡格列酮不同的是，WY14643可显著降低内脏脂肪重量和肝脏总甘油三酯含量（P<0.01），且不会增加体重增加。WY14643和吡格列酮同样增强了全身胰岛素敏感性（钳夹试验中葡萄糖输注速率分别比未处理组增加35%和37%，葡萄糖处置率分别增加22%和15%）。两种药物均增强了胰岛素介导的肌肉葡萄糖代谢指数（Rg'），并减少了肌肉甘油三酯和LCACoA的积累（P<0.05）。尽管吡格列酮在增强肌肉胰岛素敏感性方面比WY14643更有效，但其与更大程度降低肌肉LCACoA积累有关。总体而言，胰岛素介导的肌肉Rg'与LCACoA含量（r=-0.74，P=0.001）和血浆甘油三酯水平（r=-0.77，P<0.001）呈负相关。我们得出结论，尽管分别代表PPAR-α和PPAR-γ激活的WY14643和吡格列酮可能通过不同机制改变肌肉脂质供应，但两者均能显著改善高脂喂养胰岛素抵抗大鼠模型中的肌肉胰岛素作用，且这种作用与它们降低肌肉脂质积累的程度成正比。
