title: In vivo evidence that N-oleoylglycine acts independently of its conversion to oleamide.
abstract: Oleamide (cis-9-octadecenamide) is a member of an emerging class of lipid-signaling molecules, the primary fatty acid amides. A growing body of evidence indicates that oleamide mediates fundamental neurochemical processes including sleep, thermoregulation, and nociception. Nevertheless, the mechanism for oleamide biosynthesis remains unknown. The leading hypothesis holds that oleamide is synthesized from oleoylglycine via the actions of the peptide amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The present study investigated this hypothesis using pharmacologic treatments, physiologic assessments, and measurements of serum oleamide levels using a newly developed enzyme-linked immunosorbant assay (ELISA). Oleamide and oleoylglycine both induced profound hypothermia and decreased locomotion, over equivalent dose ranges and time courses, whereas, closely related compounds, stearamide and oleic acid, were essentially without effect. While the biologic actions of oleamide and oleoylglycine were equivalent, the two compounds differed dramatically with respect to their effects on serum levels of oleamide. Oleamide administration (80mg/kg) elevated blood-borne oleamide by eight-fold, whereas, the same dose of oleoylglycine had no effect on circulating oleamide levels. In addition, pretreatment with the established PAM inhibitor, disulfiram, produced modest reductions in the hypothermic responses to both oleoylglycine and oleamide, suggesting that the effects of disulfiram were not mediated through inhibition of PAM and a resulting decrease in the formation of oleamide from oleoylglycine. Collectively, these findings raise the possibilities that: (1) oleoylglycine possesses biologic activity that is independent of its conversion to oleamide and (2) the increased availability of oleoylglycine as a potential substrate does not drive the biosynthesis of oleamide.
authors.affiliation: Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, United States.
authors.forename: Shalini
authors.initials: S
authors.lastname: Chaturvedi
authors.forename: William J
authors.initials: WJ
authors.lastname: Driscoll
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Elliot
authors.forename: Martha M
authors.initials: MM
authors.lastname: Faraday
authors.forename: Neil E
authors.initials: NE
authors.lastname: Grunberg
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Mueller
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009829:Oleic Acids / Q000008:administration & dosage / Q000097:blood* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002492:Central Nervous System Depressants; C516666:N-oleoylglycine; D009829:Oleic Acids; C029407:oleylamide; D005998:Glycine