Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 29, Pages E6937-E6945Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803389115
Keywords
PM20D1; N-acyl amino acid; knockout; pain; metabolism
Categories
Funding
- NIH [DK105203, DK111916, CA172667, DK31405, DK061562]
- American Cancer Society [RSG14-242-01-TBE]
- JPB Foundation
- Calico Life Sciences, LLC
- NATIONAL CANCER INSTITUTE [R01CA172667] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK031405, K99DK105203, P30DK034854, R00DK105203, R01DK061562, R01DK031405, K99DK111916, R00DK111916] Funding Source: NIH RePORTER
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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-oleoylglutamine (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.
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