Keeping fat out of muscle - Role of Branched Amino Acids

肌肉细胞中不完全氧化的非酯化FAs （FAs）的过量积累越来越被认为是胰岛素抵抗（IR）发展的关键因果事件。与此同时，支链氨基酸（BCAAs）最近在糖尿病领域占据了前沿和中心位置，因为大型前瞻性流行病学研究中无偏见的代谢组学分析表明，血清中BCAAs的升高可在临床表现前20年预测胰岛素抵抗和糖尿病。我们发现了一种新的分子途径，将这两种观察联系起来。我们发现骨骼肌中BCAA缬氨酸的活跃分解代谢导致代谢物的旁分泌，促进FAs进入骨骼肌，并导致随后的脂肪毒性。这一途径的识别做出了许多预测，其中三个具有特别强的转化潜力，因此形成了本提案的对象：1。BCAA的分解，而不是积累，尤其是在肌肉中，会导致胰岛素抵抗。2. 特别是缬氨酸的分解是因果关系，而亮氨酸可能是保护作用。3. 治疗性地将缬氨酸分解代谢从肌肉中分流出去，可以改善胰岛素抵抗。4. 用缬氨酸治疗人类受试者，在存在过量脂肪的情况下，应该会引发胰岛素抵抗。我们提出实验来详细检验这些预测。脂质进出组织是糖尿病的核心，然而它与氨基酸，尤其是丰富的支链氨基酸的关系，却知之甚少。因此，提出的工作是确定糖尿病治疗的新靶点。

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.