Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2
Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2
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DOI：
10.1172/jci29528
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发表时间：
2007-02-01
影响因子：
15.9
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Le Bacquer, Olivier;Petroulakis, Emmanuel;Sonenberg, Nahum
与肥胖相关的最常见病理是胰岛素抵抗，它导致2型糖尿病的发病。一些研究表明，雷帕霉素（mTOR）信号通路在哺乳动物肥胖中起作用。真核生物翻译起始因子4e结合蛋白（4e - bp）是mTOR的下游效应蛋白，通过与eIF4E结合抑制翻译。我们报道，小鼠中4E-BP1和4E-BP2的联合破坏增加了它们对饮食引起的肥胖的敏感性。4E-BP1和4E-BP2双KO小鼠脂肪组织中CCAAT/增强子结合蛋白δ (C/EBP δ)、C/EBP α和PPAR γ的表达增加，加上能量消耗减少、脂肪分解减少和脂肪酸再酯化增加，导致脂肪生成加速，至少可以部分解释为肥胖增加。4E-BP1和4E-BP2双KO小鼠胰岛素抵抗的增加与肌肉、肝脏和脂肪组织中核糖体蛋白S6激酶（S6K）活性的增加和Akt信号的损伤有关。这些数据清楚地证明了4e - bp在肥胖发展中作为代谢制动器的作用，并强化了mTOR信号失调与代谢综合征发展相关的观点。
The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBP delta), C/EBP alpha, and PPAR gamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.