Chemical control of energy metabolism by N-acyl amino acids

N-酰基氨基酸对能量代谢的化学控制

• 批准号: 10357905
• 负责人: Jonathan Z Long
• 金额: $ 39.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357905
• 关键词: Ablation; Address; Amino Acids; Binding; Binding Proteins; Biochemistry; Biology; Chemicals; Data; Diabetes Mellitus; Disease; Drug Kinetics; Energy Metabolism; Energy Metabolism Pathway; Enzymes; Evaluation; Exhibits; Extracellular Protein; Family; Family member; Fatty Acids; Future; Genetic; Glucose Intolerance; Goals; Health; Homeostasis; Hydrolase; Inner mitochondrial membrane; Insulin Resistance; Lead; Leucine; Ligands; Lipids; Mediating; Medical; Membrane; Metabolic Diseases; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Obesity associated disease; Orphan; Outcome; Pathway interactions; Peptide Hydrolases; Persons; Pharmacology; Phenotype; Phenylalanine; Potential Energy; Property; Protons; Public Health; Quality of life; Regulation; Respiration; Testing; Therapeutic; Work; analog; base; blood glucose regulation; combat; crosslink; diet-induced obesity; enzyme activity; experimental study; extracellular; improved; member; metabolomics; mouse model; novel; obesity treatment

We are in the midst of an epidemic of obesity and type 2 diabetes. The discovery of new pathways of energy metabolism is critically needed to address this pressing medical problem. Using untargeted metabolomics, we have identified a new pathway of energy expenditure mediated by family of bioactive lipids called N-acyl amino acids. Certain N-acyl amino acids and stimulate mitochondrial respiration by promoting proton leak. We have also de-orphanized a novel upstream enzyme, PM20D1 (peptidase M20 domain containing 1), that functions as an extracellular N-acyl amino acid synthase/hydrolase. Pharmacological or genetic elevation of circulating N-acyl amino acids increases energy expenditure, reduces adiposity, and improves glucose homeostasis in mouse models of diet-induced obesity. However, we are still early in our understanding of N-acyl amino acids. What remains unknown is how N-acyl amino acids promote proton conductance across the inner mitochondrial membrane, what other extracellular mechanisms regulate N- acyl amino acid levels, and whether this pathway could be useful for the treatment of obesity-associated disorders. Answers are critically needed to understand the biology and therapeutic potential of this energy expenditure pathway in metabolic disease. The long-term goal of this project is to harness energy expenditure pathways for the treatment of obesity and type 2 diabetes. The overall objective of this proposal is to mechanistically dissect the regulators of the N-acyl amino acid pathway and to assess the therapeutic potential of these bioactive lipids. Our central hypothesis is that N-acyl amino acid bioactivity is regulated by both intracellular and extracellular proteins, and that this pathway can be pharmacologically leveraged for the treatment of obesity and type 2 diabetes. We will test this hypothesis via three Specific Aims: 1) Determine how N-acyl amino acids stimulate uncoupled respiration; 2) Determine the mechanisms that control circulating N-acyl amino acid levels; and 3) Evaluate the bioactivity of synthetic N-acyl amino acid analogs in diet-induced obesity mouse models. Successful completion of this proposal will provide a detailed, mechanistic understanding of the regulation and function of N-acyl amino acids in energy metabolism, as well as a pharmacological evaluation of this pathway for the treatment of obesity-associated dis- eases such as type 2 diabetes.

我们正处于肥胖症和2型糖尿病的流行中。需要发现新的能源代谢途径以解决这一紧迫的医疗问题。使用非靶向的代谢组学，我们已经确定了一种由称为N-酰基氨基酸的生物活性脂质家族介导的新能量消耗途径。某些N-酰基氨基酸并通过促进质子泄漏刺激线粒体呼吸。我们还将一种新型上游酶PM20D1（包含1个肽酶M20结构域）脱甲，该酶充当细胞外N-酰基氨基酸合酶/水解酶。循环N-酰基氨基酸的药理或遗传升高会增加能量消耗，降低肥胖，并改善饮食诱导的肥胖症小鼠模型中的葡萄糖稳态。但是，我们仍在了解N-酰基氨基酸的早期。尚不清楚的是N-酰基氨基酸如何促进整个线粒体内部膜的质子电导，其他哪些其他细胞外机制调节N-酰基氨基酸水平，以及该途径是否可用于治疗肥胖相关疾病。必须非常需要答案来了解这种能量消耗途径在代谢疾病中的生物学和治疗潜力。该项目的长期目标是利用能源消耗途径来治疗肥胖症和2型糖尿病。该提案的总体目的是机械地剖析N-酰基氨基酸途径的调节剂，并评估这些生物活性脂质的治疗潜力。我们的中心假设是，N-酰基氨基酸生物活性受细胞内和细胞外蛋白的调节，并且该途径可以在药理学上用于治疗肥胖症和2型糖尿病。我们将通过三个特定目的检验这一假设：1）确定N-酰基氨基酸如何刺激未偶联的呼吸； 2）确定控制循环N-酰基氨基酸水平的机制； 3）评估饮食诱导的肥胖小鼠模型中合成N-酰基氨基酸类似物的生物活性。该提案的成功完成将为N-酰基氨基酸在能量代谢中的调节和功能提供详细的机械理解，以及对治疗肥胖相关疾病（例如2型糖尿病）的这种途径的药理评估。