Jonathan Long

A novel enzyme-metabolite pathway of energy homeostasis

Mammalian energy metabolism is a fundamental chemical process by which the bond energy in nutrients is converted to cellular energy (ATP) and heat. All mammals possess a remarkable ability to regulate energy homeostasis by balancing energy inputs and energy outputs. However, significant portions of biochemical space regulating the physiology of energy expenditure remain poorly characterized. Here, I will discuss my recent discovery of an enzyme hormone, peptidase M20 domain containing 1 (PM20D1), that regulates energy homeostasis. Using an interdisciplinary approach combining chemistry, mass spectrometry, and mouse physiology, I found that PM20D1 is a biosynthetic enzyme for a class of lipids, the N-acyl amino acids. These metabolites function as endogenous uncouplers of mitochondrial respiration. Mice with increased circulating PM20D1, or mice treated with N-acyl amino acids, show increased energy expenditure and improved metabolic homeostasis. These data suggest that uncharted areas of enzyme and metabolite space may be rich in regulators of energy homeostasis. Lastly, I will discuss my future research interests at the intersection of chemistry and mammalian energy homeostasis.