Chemical control of energy metabolism by N-acyl amino acids

我们正处于肥胖和2型糖尿病的流行之中。为了解决这一紧迫的医学问题，迫切需要发现能量代谢的新途径。利用非靶向代谢组学，我们发现了一种新的能量消耗途径，这种途径是由被称为n -酰基氨基酸的生物活性脂质家族介导的。某些n -酰基氨基酸通过促进质子泄漏刺激线粒体呼吸。我们还去孤儿化了一种新的上游酶PM20D1（肽酶M20结构域包含1），其功能是细胞外n -酰基氨基酸合成酶/水解酶。在饮食性肥胖小鼠模型中，循环n -酰基氨基酸的药理学或遗传学升高可增加能量消耗，减少肥胖，并改善葡萄糖稳态。然而，我们对n -酰基氨基酸的了解仍处于早期阶段。目前尚不清楚的是N-酰基氨基酸如何促进线粒体内膜上的质子传导，还有什么其他细胞外机制调节N-酰基氨基酸水平，以及这一途径是否有助于治疗肥胖相关疾病。我们迫切需要答案来理解代谢疾病中这种能量消耗途径的生物学和治疗潜力。该项目的长期目标是利用能量消耗途径治疗肥胖和2型糖尿病。本提案的总体目标是机械剖析n -酰基氨基酸途径的调节因子，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 -酰基氨基酸的生物活性受到细胞内和细胞外蛋白的调节，这一途径可以在药理学上用于治疗肥胖和2型糖尿病。我们将通过三个具体目标来检验这一假设：1)确定n -酰基氨基酸如何刺激非偶联呼吸；2)确定控制循环n -酰基氨基酸水平的机制；3)评价合成的n -酰基氨基酸类似物在饮食诱导肥胖小鼠模型中的生物活性。该研究的成功完成将对n -酰基氨基酸在能量代谢中的调节和功能提供详细的机制理解，并对该途径治疗肥胖相关疾病（如2型糖尿病）进行药理学评估。

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.