Keeping fat out of muscle - Role of Branched Amino Acids

不完全氧化的非酯化脂肪酸（FAs）在肌肉细胞中的过量积累越来越被认为是胰岛素抵抗（IR）发展的关键原因。与此同时，支链氨基酸（BCAAs）最近在糖尿病领域中处于前沿和中心地位，因为大型前瞻性流行病学研究中的无偏倚代谢组学分析表明，BCAAs的血清升高可预测胰岛素抵抗和糖尿病，最早可在临床表现前20年。我们已经发现了一种新的分子途径，将这两种观察结果联系起来。我们发现，在骨骼肌中BCAA缬氨酸的活性catalysis导致促进脂肪酸进入骨骼肌的代谢产物的旁分泌，以及随后的脂毒性。这一途径的确定做出了许多预测，其中三个具有特别强的翻译潜力，因此形成了本提案的对象：1。支链氨基酸的分解，而不是积累，特别是在肌肉中，导致胰岛素抵抗。2.具体来说，缬氨酸分解是因果关系，而例如亮氨酸可能是保护性的。3.治疗性地将缬氨酸钙从肌肉中分流出来可以改善胰岛素抵抗。4.在存在过量脂肪的情况下，用缬氨酸治疗人类受试者应该引发胰岛素抵抗。我们提出了实验来测试这些预测的细节。脂质进出组织是糖尿病的核心，但它与氨基酸，特别是丰富的支链氨基酸的关系却知之甚少。因此，拟议的工作将确定治疗糖尿病的新靶点。

Excess accumulation of incompletely oxidized non-esterified FAs (FAs) in muscle cells is increasingly appreciated to be a critical causal event in the development of insulin resistance (IR). In parallel, branched chain amino acids (BCAAs) have recently moved front and center in the field of diabetes, as unbiased metabolomic profiling in large prospective epidemiological studies have shown that serum elevations in BCAAs predict insulin resistance and diabetes as much as 20 years prior to clinical presentation. We have uncovered a novel molecular pathway that links these two observations. We find that active catabolism of the BCAA valine in skeletal muscle causes the paracrine secretion of metabolites that promote entry of FAs into skeletal muscle, and subsequent lipotoxicity. The identification of this pathway makes numerous predictions, three of which have especially strong translational potential and thus form the object of this proposal: 1. BCAA breakdown, rather than accumulation, and specifically in muscle, causes insulin resistance. 2. Specifically Valine breakdown is causal, whereas for example leucine may be protective. 3. Therapeutic shunting of valine catabolism away from muscle should improve insulin resistance. 4. Treating human subjects with valine, in the presence of excess fat, should trigger insulin resistance. We propose experiments to test these predictions in detail. Lipid trafficking in and out of tissues is at the heart of diabetes, and yet its relationship to trafficking amino acids, and especially the abundant BCAAs, is little understood. The proposed work thus stands to identify a novel targets for the treatment of diabetes.