A potential link between muscle peroxisome proliferator-activated receptor-α signaling and obesity-related diabetes
A potential link between muscle peroxisome proliferator-activated receptor-α signaling and obesity-related diabetes
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DOI：
10.1016/j.cmet.2005.01.006
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发表时间：
2005-02-01
期刊：
影响因子：
29
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Finck, BN;Bernal-Mizrachi, C;Kelly, DP
使用功能获得和功能丧失方法评估过氧化物酶体增殖物激活受体α (PPAR α)在胰岛素抵抗性糖尿病发展中的作用。在肌肉中过度表达PPAR α的转基因小鼠（MCK-PPAR α小鼠）出现了葡萄糖耐受不良，尽管它们没有受到饮食引起的肥胖的保护。相反，在肥胖的情况下，PPAR α缺失的小鼠免受饮食诱导的胰岛素抵抗的影响。在骨骼肌中，MCK-PPAR α小鼠表现出脂肪酸氧化率增加，amp激活的蛋白激酶活性降低，胰岛素刺激的葡萄糖摄取减少，而关键胰岛素信号蛋白的磷酸化状态没有改变。这些对肌肉葡萄糖摄取的影响涉及GLUT4基因的转录抑制。脂肪酸氧化或线粒体呼吸偶联的药理学抑制可阻止PPAR α对GLUT4表达和葡萄糖稳态的影响。这些结果确定PPAR α驱动的肌肉脂肪酸氧化和能量学改变是肥胖与葡萄糖耐受不良和胰岛素抵抗之间的潜在联系。
The role of the peroxisome proliferator-activated receptor-alpha (PPAR alpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPAR alpha in muscle (MCK-PPAR alpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPAR alpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPAR alpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPAR alpha on GLUT4 expression and glucose homeostasis. These results identify PPAR alpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.