Author:
Long Jonathan Z.,Roche Alexander M.,Berdan Charles A.,Louie Sharon M.,Roberts Amanda J.,Svensson Katrin J.,Dou Florence Y.,Bateman Leslie A.,Mina Amir I.,Deng Zhaoming,Jedrychowski Mark P.,Lin Hua,Kamenecka Theodore M.,Asara John M.,Griffin Patrick R.,Banks Alexander S.,Nomura Daniel K.,Spiegelman Bruce M.
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.
Funder
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
American Cancer Society
HHS | NIH | National Cancer Institute
JPB Foundation
Calico, LLC
Publisher
Proceedings of the National Academy of Sciences
Cited by
45 articles.
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