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. Epub 2016 Jun 30.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / metabolism*
  • Amidohydrolases / metabolism*
  • Amino Acids / blood
  • Animals
  • Cell Respiration
  • Energy Metabolism
  • Fatty Acids / blood
  • Glucose / metabolism
  • Homeostasis
  • Male
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Thermogenesis*


  • Amino Acids
  • Fatty Acids
  • Mitochondrial Proteins
  • Amidohydrolases
  • PM20D1 protein, mouse
  • Glucose