2. Academic Validation
  3. The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

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

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.

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