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.

肌肉细胞中不完全氧化的非酯化 FA (FA) 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 (BCAA) 最近已成为糖尿病领域的前沿和中心，大型前瞻性流行病学研究中的无偏代谢组学分析表明，血清中 BCAA 的升高早在 20 年前就可预测胰岛素抵抗和糖尿病。临床表现。我们发现了一种将这两个观察结果联系起来的新分子途径。我们发现骨骼肌中 BCAA 缬氨酸的活跃分解代谢会导致代谢物的旁分泌分泌，从而促进 FA 进入骨骼肌，并产生随后的脂毒性。该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，因此构成了本提议的目标： 1. BCAA 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，缬氨酸分解是因果性的，而亮氨酸分解可能是保护性的。 3. 治疗性地将缬氨酸分解代谢从肌肉中分流应该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，但人们对其与氨基酸（尤其是丰富的支链氨基酸）运输的关系知之甚少。因此，拟议的工作旨在确定治疗糖尿病的新靶点。