LAUSR

Significance Bioactive lipids control a wide variety of physiologic processes. We have recently identified a branch of bioactive lipid signaling mediated by N-acyl amino acids (NAAs) and the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Here we generate and characterize mice globally deficient in PM20D1. These PM20D1-KO mice have bidirectional changes in NAA levels in blood and tissues and exhibit a variety of metabolic and nociceptive phenotypes. Our findings elucidate the endogenous physiologic functions for NAA signaling in vivo and suggest PM20D1 inhibitors might be useful for the treatment of pain. 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.