2. Academic Validation
  3. Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception

Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception

  • Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6937-E6945. doi: 10.1073/pnas.1803389115.
Jonathan Z Long 1 2,  Alexander M Roche 1 2,  Charles A Berdan 3 4 5,  Sharon M Louie 3 4 5,  Amanda J Roberts 6,  Katrin J Svensson 1 2,  Florence Y Dou 1 2,  Leslie A Bateman 3 4 5,  Amir I Mina 7,  Zhaoming Deng 7,  Mark P Jedrychowski 1 2,  Hua Lin 8,  Theodore M Kamenecka 8,  John M Asara 9,  Patrick R Griffin 8,  Alexander S Banks 7,  Daniel K Nomura 3 4 5,  Bruce M Spiegelman 10 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
  • 3 Department of Chemistry, University of California, Berkeley, CA 94720.
  • 4 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
  • 5 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720.
  • 6 Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037.
  • 7 Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA 02115.
  • 8 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458.
  • 9 Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA 02115.
  • 10 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; Bruce_Spiegelman@dfci.harvard.edu.
PMID: 29967167 DOI: 10.1073/pnas.1803389115
Abstract

N-acyl Amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating Enzyme peptidase M20 domain-containing 1 (PM20D1). Global PM20D1-KO mice have dramatically reduced NAA hydrolase/synthase activities in tissues and blood with concomitant bidirectional dysregulation of endogenous NAAs. Compared with control Animals, PM20D1-KO mice exhibit a variety of metabolic and pain phenotypes, including Insulin resistance, altered body temperature in cold, and antinociceptive behaviors. Guided by these phenotypes, we identify N-oleoyl-glutamine (C18:1-Gln) as a key PM20D1-regulated NAA. In addition to its mitochondrial uncoupling bioactivity, C18:1-Gln also antagonizes certain members of the transient receptor potential (TRP) calcium channels including TRPV1. Direct administration of C18:1-Gln to mice is sufficient to recapitulate a subset of phenotypes observed in PM20D1-KO Animals. These data demonstrate that PM20D1 is a dominant enzymatic regulator of NAA levels in vivo and elucidate physiologic functions for NAA signaling in metabolism and nociception.

Keywords

N-acyl amino acid; PM20D1; knockout; metabolism; pain.

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