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Cell. 2016 Jul 14;166(2):424-435. doi: 10.1016/j.cell.2016.05.071. Epub 2016 Jun 30.

The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.

Author information

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: dnomura@berkeley.edu.
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: bruce_spiegelman@dfci.harvard.edu.

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.

PMID:
27374330
PMCID:
PMC4947008
DOI:
10.1016/j.cell.2016.05.071
[Indexed for MEDLINE]
Free PMC Article

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