Muscle-specific Pparg deletion causes insulin resistance
Muscle-specific Pparg deletion causes insulin resistance
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DOI：
10.1038/nm956
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发表时间：
2003-12-01
期刊：
影响因子：
82.9
通讯作者：
Olefsky, J
中科院分区：
文献类型：
--
作者：
Hevener, AL;He, WM;Olefsky, J
噻唑烷二酮（TZD）是胰岛素增敏药物，并且是核过氧化物酶体增殖物激活受体-γ（PPAR-γ）的有效激动剂。虽然肌肉是负责胰岛素刺激的葡萄糖处置的主要器官，但是PPAR-gamma在脂肪组织中比在肌肉中更高地表达。为了解决这个问题，我们使用Cre-loxP系统敲除小鼠骨骼肌中编码PPAR-gamma的基因Pparg。早在4个月大时，肌肉中靶向破坏PPAR-gamma的小鼠就表现出葡萄糖不耐受和进行性胰岛素抵抗。采用高胰岛素-正葡萄糖钳夹技术，体内胰岛素刺激的葡萄糖处置率（IS-GDR）降低了约80%，TZD治疗3周后没有变化。这些作用揭示了肌肉PPAR-gamma在维持骨骼肌胰岛素作用、胰岛素抵抗的病因学和TZD作用中的关键作用。
Thiazolidinediones (TZDs) are insulin- sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator- activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin- stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre- loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic- euglycemic clamp technique, the in vivo insulin- stimulated glucose disposal rate (IS- GDR) was reduced by similar to80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.