Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle
Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle
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DOI：
10.1073/pnas.2536828100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Evans, RM
中科院分区：
文献类型：
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作者：
He, WM;Barak, Y;Evans, RM
X综合征以肥胖、胰岛素抵抗(IR)、血脂异常和其他代谢异常为特征，对抗糖尿病药物(TZDS)有反应。过氧化物酶体增殖物激活受体(PPAR)γ是TZDS的靶标之一，在脂肪细胞中大量表达，提示该组织在IR的病因和治疗中起着重要作用。靶向缺失脂肪组织中的PPARGamma导致明显的脂肪细胞减少和肥大，血浆游离脂肪酸和甘油三酯水平升高，血浆瘦素和ACRP30水平下降。此外，还观察到肝脏糖生成增加和胰岛素抵抗。尽管有这些缺陷，血糖、葡萄糖和胰岛素耐量以及胰岛素刺激的肌肉葡萄糖摄取量都与对照组小鼠相当。然而，靶标小鼠明显更易患高脂饮食诱导的脂肪变性、高胰岛素血症和IR。令人惊讶的是，TZD治疗有效地逆转了肝脏IR，而它未能降低血浆游离脂肪酸。这些结果表明，X综合征可能由可分离的PPAR依赖成分组成，其起源和治疗部位可能位于不同的组织中。
Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) gamma, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPARgamma in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, and decreased levels of plasma leptin and ACRP30. In addition, increased hepatic glucogenesis and IR were observed. Despite these defects, blood glucose, glucose and insulin tolerance, and insulin-stimulated muscle glucose uptake were all comparable to those of control mice. However, targeted mice were significantly more susceptible to high-fat diet-induced steatosis, hyperinsulinemia, and IR. Surprisingly, TZD treatment effectively reversed liver IR, whereas it failed to lower plasma free fatty acids. These results suggest that syndrome X may be comprised of separable PPARgamma-dependent components whose origins and therapeutic sites may reside in distinct tissues.