title: The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.
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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katrin J
authors.initials: KJ
authors.lastname: Svensson
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bateman
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Kamenecka
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Isha A
authors.initials: IA
authors.lastname: Lokurkar
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Rao
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joao A
authors.initials: JA
authors.lastname: Paulo
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: 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.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: 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.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism*; D000596:Amino Acids / Q000097:blood; D000818:Animals; D019069:Cell Respiration; D004734:Energy Metabolism; D005227:Fatty Acids / Q000097:blood; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D022722:Thermogenesis
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D000581:Amidohydrolases; C000612608:PM20D1 protein, mouse; D005947:Glucose