Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.
Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.
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DOI：
10.1016/j.molmet.2016.08.001
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发表时间：
2016-10
影响因子：
8.1
通讯作者：
Patti ME
中科院分区：
文献类型：
--
作者：
Lerin C;Goldfine AB;Boes T;Liu M;Kasif S;Dreyfuss JM;De Sousa-Coelho AL;Daher G;Manoli I;Sysol JR;Isganaitis E;Jessen N;Goodyear LJ;Beebe K;Gall W;Venditti CP;Patti ME
肥胖和 2 型糖尿病 (T2D) 患者的血浆支链氨基酸 (BCAA) 水平持续升高，并且还可以前瞻性预测 T2D。然而，BCAA 在胰岛素抵抗和 T2D 发病机制中的作用仍不清楚。为了确定与胰岛素抵抗相关的途径，我们对 41 名糖耐量正常的人和 11 名 T2D 患者的骨骼肌进行了全面的基因表达和代谢组学分析，这些患者的胰岛素敏感性范围广泛（SI，0.49 至 14.28）。我们研究了 BCAA 酶甲基丙二酸单酰辅酶 A 变位酶 (Mut) 杂合的培养细胞和小鼠，并评估了改变的 BCAA 通量对脂质和葡萄糖稳态的影响。我们的数据表明，胰岛素抵抗人群的肌肉中支链氨基酸代谢和脂肪酸氧化受到干扰。培养细胞中支链氨基酸通量的实验改变同样可以调节脂肪酸氧化。小鼠的突变杂合性会改变体内肌肉脂质代谢，导致肌肉甘油三酯积累增加、血浆葡萄糖增加、高胰岛素血症以及高脂肪喂养后体重增加。我们的数据表明，肌肉 BCAA 分解代谢受损可能通过干扰氨基酸和脂肪酸代谢而导致胰岛素抵抗的发展，并表明针对 BCAA 代谢可能有望预防或治疗 T2D。人类胰岛素抵抗与肌肉支链氨基酸代谢紊乱有关。 BCAA 代谢流的实验调节可改变体外脂肪酸氧化。突变杂合导致小鼠体重增加和肌肉 TAG 积累。
Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D. Human insulin resistance is associated with perturbed muscle BCAA metabolism. Experimental modulation of BCAA metabolic flux alters fatty acid oxidation in vitro. Mut heterozygosis leads to increased body weigh and muscle TAG accumulation in mice.
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影响因子：
8.2
作者：
Glynn EL;Piner LW;Huffman KM;Slentz CA;Elliot-Penry L;AbouAssi H;White PJ;Bain JR;Muehlbauer MJ;Ilkayeva OR;Stevens RD;Porter Starr KN;Bales CW;Volpi E;Brosnan MJ;Trimmer JK;Rolph TP;Newgard CB;Kraus WE
通讯作者：
Kraus WE
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：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
影响因子：
--
作者：
Chandler RJ;Sloan J;Fu H;Tsai M;Stabler S;Allen R;Kaestner KH;Kazazian HH;Venditti CP
通讯作者：
Venditti CP
影响因子：
9.3
作者：
Goldfine, Allison B.;Gerwien, Robert W.;Patti, Mary Elizabeth
通讯作者：
Patti, Mary Elizabeth