The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

  • Cell. 2016 Jul 14;166(2):424-435. doi: 10.1016/j.cell.2016.05.071.
Jonathan Z Long  1 ,  Katrin J Svensson  1 ,  Leslie A Bateman  2 ,  Hua Lin  3 ,  Theodore Kamenecka  3 ,  Isha A Lokurkar  4 ,  Jesse Lou  4 ,  Rajesh R Rao  1 ,  Mi Ra Chang  3 ,  Mark P Jedrychowski  1 ,  Joao A Paulo  5 ,  Steven P Gygi  5 ,  Patrick R Griffin  3 ,  Daniel K Nomura  6 ,  Bruce M Spiegelman  7
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 2. Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 3. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 6. Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].
  • 7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 27374330 DOI: 10.1016/j.cell.2016.05.071
Abstract

Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of Fatty Acids and Amino acids to generate N-acyl Amino acids and also the reverse hydrolytic reaction. N-acyl Amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl Amino acids in blood. Lastly, administration of N-acyl Amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating Obesity and associated disorders.