Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome
Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome
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DOI：
10.1073/pnas.0306981100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Sakai, J
中科院分区：
文献类型：
--
作者：
Tanaka, T;Yamamoto, J;Sakai, J
在这项研究中，我们通过使用亚型选择性激动剂，确定了过氧化物酶体增殖物激活受体β/增量(PPARDelta)在代谢稳态中的作用。用Affymetrix寡核苷酸微阵列对PPARDelta亚型选择性激动剂GW501516处理的大鼠L6肌管的分析表明，PPARDelta通过调节与脂肪酸运输、p-氧化和线粒体呼吸有关的基因来控制脂肪酸氧化。在GW501516处理的小鼠骨骼肌中也观察到了类似的PPARDelta介导的基因激活。因此，GW501516处理诱导了L6肌管和小鼠骨骼肌中的脂肪酸β氧化。给喂食高脂饮食的小鼠服用GW501516可以改善饮食诱导的肥胖和胰岛素抵抗，伴随着提高代谢率和脂肪酸β-氧化、线粒体增殖和骨骼肌脂滴显著减少的效果。尽管与赋形剂治疗的小鼠相比，GW501516的体重变化不大，但GW501516治疗也显著改善了糖尿病，这一点从遗传肥胖的ob/ob小鼠的血糖和血胰岛素水平的降低中可见一斑。这些数据表明，PPARDelta对于控制骨骼肌中的脂肪酸氧化程序至关重要，从而通过激活它来改善肥胖动物的肥胖和胰岛素抵抗。
In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, p-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid beta-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.