Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.
Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.
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DOI：
10.1016/j.molmet.2021.101261
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发表时间：
2021-10
影响因子：
8.1
通讯作者：
Newgard CB
中科院分区：
文献类型：
--
作者：
White PJ;McGarrah RW;Herman MA;Bain JR;Shah SH;Newgard CB
几十年来，人们已经认识到肥胖和胰岛素抵抗与支链和芳香氨基酸循环水平升高以及甘氨酸水平降低之间存在密切关联。最近，人类代谢组学和遗传学研究已经证实并扩展了这些观察结果，同时临床前研究的激增也确定了与氨基酸稳态扰动相关的机制——这些事件如何与葡萄糖和脂质代谢失调相关，以及支链氨基酸 (BCAA) 的升高如何参与 2 型胰岛素抵抗的发展 糖尿病（T2D）和其他心脏代谢疾病和病症。在人类队列中，BCAA 和相关代谢物现已被确定为肥胖、胰岛素抵抗、T2D 和心血管疾病最强的生物标志物之一。在肥胖啮齿类动物模型中，通过饲喂 BCAA 限制饮食或通过激活 BCAA 分解代谢中的限速酶支链酮酸脱氢酶 (BCKDH) 来降低 BCAA 和支链酮酸 (BCKA) 水平，对葡萄糖和脂质稳态具有明显的有益作用，但 BCAA 限制的影响较小 对人类 T2D 受试者的短期研究的影响。用富含蔗糖或果糖的饮食喂养大鼠会诱导肝脏中 ChREBP 转录因子增加 BCKDH 激酶 (BDK) 的表达并抑制其磷酸酶 (PPM1K) 的表达，从而导致 BCKDH 失活并激活关键的脂肪生成酶 ATP-柠檬酸裂解酶 (ACLY)。支链氨基酸、葡萄糖和脂质代谢之间的这些以及其他新兴联系激发了对支链氨基酸和相关代谢物在心脏代谢疾病发展中可能的因果作用的持续研究。支链氨基酸 (BCAA) 与代谢疾病表型相关。肥胖驱动的支链氨基酸代谢变化会影响脂质和葡萄糖代谢。 BCAA 和支链酮酸 (BCKA) 对组织功能有直接影响。 BCAA 代谢的激活可改善葡萄糖和脂质稳态。
A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades. More recently, human metabolomics and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in the perturbation of amino acid homeostasis— how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids (BCAA) may participate in the development of insulin resistance, type 2 diabetes (T2D), and other cardiometabolic diseases and conditions. In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases. Lowering of BCAA and branched-chain ketoacid (BCKA) levels by feeding BCAA-restricted diet or by the activation of the rate-limiting enzyme in BCAA catabolism, branched-chain ketoacid dehydrogenase (BCKDH), in rodent models of obesity have clear salutary effects on glucose and lipid homeostasis, but BCAA restriction has more modest effects in short-term studies in human T2D subjects. Feeding of rats with diets enriched in sucrose or fructose result in the induction of the ChREBP transcription factor in the liver to increase expression of the BCKDH kinase (BDK) and suppress the expression of its phosphatase (PPM1K) resulting in the inactivation of BCKDH and activation of the key lipogenic enzyme ATP-citrate lyase (ACLY). These and other emergent links between BCAA, glucose, and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in the development of cardiometabolic diseases. Branched-chain amino acids (BCAA) are associated with metabolic disease phenotypes. Obesity-driven changes in BCAA metabolism affect lipid and glucose metabolism. BCAA and branched-chain ketoacids (BCKA) have direct effects on tissue functions. Activation of BCAA metabolism improves glucose and lipid homeostasis.
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影响因子：
3.7
作者：
Macotela Y;Emanuelli B;Bång AM;Espinoza DO;Boucher J;Beebe K;Gall W;Kahn CR
通讯作者：
Kahn CR
影响因子：
37.8
作者：
Cheng S;Rhee EP;Larson MG;Lewis GD;McCabe EL;Shen D;Palma MJ;Roberts LD;Dejam A;Souza AL;Deik AA;Magnusson M;Fox CS;O'Donnell CJ;Vasan RS;Melander O;Clish CB;Gerszten RE;Wang TJ
通讯作者：
Wang TJ
DOI：
10.1152/ajpendo.00334.2019
发表时间：
2020-02-01
影响因子：
5.1
作者：
McGarrah, Robert W.;Zhang, Guo-Fang;Newgard, Christopher B.
通讯作者：
Newgard, Christopher B.
DOI：
10.1152/ajpendo.00630.2012
发表时间：
2013-06-01
影响因子：
5.1
作者：
Lackey, Denise E.;Lynch, Christopher J.;Adams, Sean H.
通讯作者：
Adams, Sean H.
影响因子：
8.2
作者：
Kadakia, Rachel;Nodzenski, Michael;Lowe, William L., Jr.
通讯作者：
Lowe, William L., Jr.