Keeping fat out of muscle - Role of Branched Amino Acids

肌肉细胞中不完全氧化的非酯化脂肪酸(FAs)的过度积累被认为是胰岛素抵抗(IR)发生的关键原因。与此同时，支链氨基酸(BCAA)最近已成为糖尿病领域的前沿和中心，因为大型前瞻性流行病学研究中的无偏代谢组分析表明，BCAA的血清升高最早在临床表现前20年预测胰岛素抵抗和糖尿病。我们已经发现了一条连接这两个观察结果的新的分子途径。我们发现，骨骼肌中支链氨基酸valine的活跃分解代谢导致代谢物的旁分泌，促进FAs进入骨骼肌，从而导致随后的脂毒性。对这一途径的识别做出了许多预测，其中三个预测具有特别强的翻译潜力，因此形成了本提案的目标：1.导致胰岛素抵抗的是支链氨基酸的分解，而不是积累，特别是肌肉中的积累。2.明确地说，Valine的分解是导致的，而例如亮氨酸可能是保护性的。3.治疗性地将缬氨酸分解代谢从肌肉中分流，可改善胰岛素抵抗。4.在脂肪过多的情况下，用缬氨酸治疗人类受试者，应该会引发胰岛素抵抗。我们提出了实验来详细测试这些预测。组织内外的脂肪运输是糖尿病的核心，但它与氨基酸运输的关系，特别是与丰富的支链氨基酸的关系，却鲜为人知。因此，这项拟议的工作将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.