Branched-chain amino acids in metabolic signalling and insulin resistance.
Branched-chain amino acids in metabolic signalling and insulin resistance.
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DOI：
10.1038/nrendo.2014.171
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发表时间：
2014-12
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支链氨基酸（BCAA）是重要的营养信号，具有直接和间接的影响。通常，支链氨基酸已被报道介导抗肥胖作用，特别是在啮齿动物模型中。然而，BCAA的循环水平往往在肥胖个体中增加，并且与更差的代谢健康和未来的胰岛素抵抗或2型糖尿病（T2 DM）相关。一种假设的BCAA水平升高与2型糖尿病相关的机制涉及亮氨酸介导的哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）的激活，这导致胰岛素信号在早期阶段解偶联。BCAA代谢障碍模型提出，有丝分裂毒性代谢物（而非BCAA本身）的蓄积促进了与T2 DM相关的β细胞线粒体功能障碍、应激信号传导和细胞凋亡。或者，胰岛素抵抗可能通过增加胰岛素通常抑制的蛋白质降解和/或通过引起某些组织中有效BCAA氧化代谢的损害来促进氨基酸血症。是否以及如何受损的支链氨基酸代谢可能会发生在肥胖症是讨论这一审查。需要研究BCAA代谢中个体和模型依赖性差异的作用，因为几个基因（BCKDHA、PPM 1 K、IVD和KLF 15）已被指定为人类肥胖和/或T2 DM的候选基因，并且在肥胖和T2 DM动物模型中检测到组织特异性支链酮酸脱氢酶复合物活性的不同表型。
Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.