Regulation of peroxisome proliferator-activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis
Regulation of peroxisome proliferator-activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis
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DOI：
10.2337/diabetes.53.11.2748
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发表时间：
2004-11-01
期刊：
影响因子：
7.7
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Kim, JE;Chen, J
脂肪细胞分化是一个发育过程，对代谢稳态和营养信号传导至关重要。哺乳动物雷帕霉素靶点（mTOR）介导营养信号，调节细胞生长、增殖和多种细胞分化。据报道，雷帕霉素是mTOR的抑制剂和免疫抑制剂，可阻止脂肪细胞分化，但这种现象的机制尚不清楚。在这里，我们发现mTOR在3T3-L1前脂肪细胞分化中起着关键作用，并且mTOR激酶活性是这一过程所必需的。雷帕霉素通过直接靶向ppar - γ的反式激活活性，特异性地破坏了CCAAT/增强子结合蛋白- α和过氧化物酶体增殖体激活受体- γ (PPAR-gamma)这两个脂肪生成关键转录因子之间的正转录反馈环。此外，我们首次证明ppar - γ活性依赖于氨基酸的充足性，揭示了营养状况和脂肪形成之间的分子联系。我们的进一步研究结果使我们提出了一个模型，其中mTOR途径和磷脂酰肌醇3-激酶/Akt途径平行作用，分别通过介导营养可用性和胰岛素信号来调节脂肪形成过程中的ppar - γ激活。有趣的是，曲格列酮（一种噻唑烷二酮类药物）逆转了雷帕霉素和氨基酸剥夺的抑制作用，这表明噻唑烷二酮类药物在对抗雷帕霉素作为免疫抑制剂的某些副作用方面具有治疗价值。
Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process. Rapamycin specifically disrupted the positive transcriptional feedback loop between CCAAT/enhancer-binding protein-alpha and peroxisome proliferator-activated receptor-gamma (PPAR-gamma), two key transcription factors in adipogenesis, by directly targeting the transactivation activity of PPAR-gamma. In addition, we demonstrate for the first time that PPAR-gamma activity is dependent on amino acid sufficiency, revealing a molecular link between nutrient status and adipogenesis. The results of our further investigation have led us to propose a model in which the mTOR pathway and the phosphatidylinositol 3-kinase/Akt pathway act in parallel to regulate PPAR-gamma activation during adipogenesis by mediating nutrient availability and insulin signals, respectively. It is interesting that troglitazone (a thiazolidinedione drug) reversed the inhibitory effects of rapamycin and amino acid deprivation, implicating therapeutic values of thiazolidinedione drugs to counter certain side effects of rapamycin as an immunosuppressant.