Chemical control of energy metabolism by N-acyl amino acids

我们正处于肥胖症和2型糖尿病的流行之中。为了解决这一紧迫的医学问题，迫切需要发现新的能量代谢途径。利用非靶向代谢组学，我们已经确定了一种被称为N-酰基氨基酸的生物活性脂类家族介导的新的能量消耗途径。某些N-酰基氨基酸，并通过促进质子泄漏来刺激线粒体呼吸。我们还去孤儿了一种新的上游酶PM20D1(肽酶M20结构域包含1)，它的功能是胞外N-酰基氨基酸合成酶/水解酶。在饮食诱导肥胖的小鼠模型中，循环N-酰基氨基酸的药理或遗传升高增加了能量消耗，减少了肥胖，并改善了葡萄糖稳态。然而，我们对N-酰基氨基酸的理解还处于早期阶段。目前尚不清楚N-酰基氨基酸如何促进跨线粒体内膜的质子电导，还有什么细胞外机制调节N-酰基氨基酸水平，以及这一途径是否有助于肥胖相关疾病的治疗。要了解代谢疾病中这种能量消耗途径的生物学和治疗潜力，答案是至关重要的。该项目的长期目标是利用能量消耗途径治疗肥胖症和2型糖尿病。这项提案的总体目标是从机械上剖析N-酰基氨基酸途径的调节因子，并评估这些生物活性脂类的治疗潜力。我们的中心假设是N-酰基氨基酸的生物活性受细胞内和细胞外蛋白质的调节，这一途径可以在药物上用于肥胖症和2型糖尿病的治疗。我们将通过三个具体目标来验证这一假设：1)确定N-酰基氨基酸如何刺激非偶联呼吸；2)确定控制循环中N-酰基氨基酸水平的机制；以及3)在饮食诱导的肥胖小鼠模型中评估合成的N-酰基氨基酸类似物的生物活性。这项提议的成功完成将提供对N-酰基氨基酸在能量代谢中的调节和功能的详细的、机械的理解，以及对这一治疗肥胖相关疾病(如2型糖尿病)的途径的药理学评估。

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.