Keeping fat out of muscle - Role of Branched Amino Acids

保持肌肉中的脂肪——支链氨基酸的作用

基本信息

批准号：
10186735
负责人：
Zoltan P Arany
金额：
$ 47.61万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186735
关键词：
Address Affect Amino Acids Anabolism Blood Vessels Branched-Chain Amino Acids Catabolism Clinical Consumption Data Development Diabetes Mellitus Diet Dietary Supplementation Endothelial Cells Endothelium Enzymes Event Eye FRAP1 gene Fatty Acids Fatty acid glycerol esters Genetic Glucose Clamp Heart Homeostasis Human Infusion procedures Insulin Resistance Investigation Isoleucine Leucine Link Lipids Liver Medicine Metabolic Modeling Molecular Morbidity - disease rate Muscle Muscle Cells Nature Oxides Pathway interactions Phosphoric Monoester Hydrolases Physiological Plant Roots Process Proteins Publishing Randomized Rodent Role Serum Shunt Device Skeletal Muscle Testing Therapeutic Tissues Valine Work amino acid metabolism base deprivation diabetic diabetogenic epidemiology study experimental study fatty acid transport feeding gain of function gene therapy gut microbes healthy volunteer high reward human subject improved inhibitor/antagonist insulin sensitivity interest link protein lipid transport loss of function metabolomics mortality novel paracrine prevent prospective success trafficking

项目摘要

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.

越来越多地认为，肌肉细胞中未完全氧化的非酯化FA（FAS）的过量积累被越来越多地成为胰岛素抵抗（IR）发展的关键因果事件。同时，分支链氨基酸（BCAA）最近在糖尿病领域的前端和中心移动，因为在大型前瞻性流行病学研究中无偏的代谢组分析表明，BCAAS的血清升高预测胰岛素抵抗和糖尿病的糖尿病高达20年。我们发现了一种新的分子途径，该途径将这两个观察结果联系起来。我们发现，骨骼肌中BCAA缬氨酸的活性分解代谢会导致代谢产物的旁分泌分泌，从而促进FAS进入骨骼肌，然后促进脂肪毒性。该途径的识别提出了许多预测，其中三个具有特别强大的翻译潜力，因此构成了该提案的对象：1。BCAA崩溃，而不是积累，尤其是在肌肉中，会引起胰岛素抵抗。 2。特别是瓣膜分解是因果关系，而例如亮氨酸可能具有保护性。 3。从肌肉远离缬氨酸分解代谢的治疗性分流应改善胰岛素抵抗。 4。在存在多余脂肪的情况下，用瓣膜治疗人类受试者应引发胰岛素抵抗。我们建议实验以详细测试这些预测。脂质运输进出组织是糖尿病的核心，但它与贩运氨基酸的关系，尤其是大量的BCAA，却几乎没有理解。因此，提出的工作旨在确定糖尿病治疗的新目标。