Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity
Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity
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DOI：
10.1172/jci77361
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发表时间：
2015-08-01
影响因子：
15.9
通讯作者：
Kennedy, Brian K.
中科院分区：
文献类型：
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作者：
Tsai, Shihyin;Sitzmann, Joanna M.;Kennedy, Brian K.
真核翻译起始因子4 E结合蛋白1（4 E-BP 1）是mTOR复合物1（mTORC 1）的关键下游效应子，其通过隔离翻译起始因子eIF 4 E来抑制帽依赖性mRNA翻译起始。mTORC 1信号传导减少与寿命延长和代谢稳态改善有关，但介导这些益处的下游靶点尚不清楚。在这里，我们证明了小鼠骨骼肌中增强的4 E-BP 1活性可以防止年龄和饮食诱导的胰岛素抵抗和代谢率下降。转基因动物表现出增加的能量消耗;改变脂肪组织分布，包括减少的白色脂肪堆积和保留的棕色脂肪质量;并保护免于肝脂肪变性。骨骼肌特异性4 E-BP 1通过增加过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）的翻译和增强呼吸功能直接介导代谢保护。非细胞自主保护是通过保存棕色脂肪组织代谢，这是增加在4 E-BP 1转基因动物在正常衰老和饮食诱导的2型糖尿病的反应。脂肪表型可能来源于已知肌因子FGF 21的增强的骨骼肌表达和分泌。与骨骼肌不同，增强的脂肪特异性4 E-BP 1活性在相同的挑战下不是保护性的，而是有害的。这些发现表明，骨骼肌中4 E-BP 1的调节可能是mTORC 1控制代谢的重要渠道。
Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) and enhanced respiratory function. Non-cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism.