Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Nat Metab. 2023 Apr;5(4):589-606. doi: 10.1038/s42255-023-00794-y. Epub 2023 Apr 26.
Elevated levels of plasma branched-chain amino acids (BCAAs) have been associated with insulin resistance and type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves insulin sensitivity. Here we show that modulation of BCKDH in skeletal muscle, but not liver, affects fasting plasma BCAAs in male mice. However, despite lowering BCAAs, increased BCAA oxidation in skeletal muscle does not improve insulin sensitivity. Our data indicate that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. These findings suggest potential concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
自 20 世纪 60 年代以来，血浆支链氨基酸（BCAAs）水平升高与胰岛素抵抗和 2 型糖尿病有关。BCAA 氧化的限速酶支链α-酮酸脱氢酶（BCKDH）的药理学激活可降低血浆 BCAAs 并改善胰岛素敏感性。在这里，我们表明，BCKDH 在骨骼肌中的调节，而不是在肝脏中，会影响雄性小鼠的空腹血浆 BCAAs。然而，尽管降低了 BCAAs，但骨骼肌中增加的 BCAA 氧化并不能改善胰岛素敏感性。我们的数据表明，骨骼肌控制着血浆 BCAAs，降低空腹血浆 BCAAs 不足以改善胰岛素敏感性，并且骨骼肌和肝脏都不能解释 BCKDH 药理学激活所带来的胰岛素敏感性改善。这些发现表明，多个组织在调节 BCAAs 代谢以改变胰岛素敏感性方面可能存在协同作用。
