title: Fever Is Mediated by Conversion of Endocannabinoid 2-Arachidonoylglycerol to Prostaglandin E2.
abstract: Fever is a common response to inflammation and infection. The mechanism involves prostaglandin E2 (PGE2)-EP3 receptor signaling in the hypothalamus, which raises the set point of hypothalamic thermostat for body temperature, but the lipid metabolic pathway for pyretic PGE2 production remains unknown. To reveal the molecular basis of fever initiation, we examined lipopolysaccharides (LPS)-induced fever model in monoacylglycerol lipase (MGL)-deficient (Mgll-/-) mice, CB1 receptor-MGL compound-deficient (Cnr1-/-Mgll-/-) mice, cytosolic phospholipase A2α (cPLA2α)-deficient (Pla2g4a-/-) mice, and diacylglycerol lipase α (DGLα)-deficient (Dagla-/-) mice. Febrile reactions were abolished in Mgll-/- and Cnr1-/-Mgll-/- mice, whereas Cnr1-/-Mgll+/+, Pla2g4a-/- and Dagla-/- mice responded normally, demonstrating that MGL is a critical enzyme for fever, which functions independently of endocannabinoid signals. Intracerebroventricular administration of PGE2 caused fever similarly in Mgll-/- and wild-type control mice, suggesting a lack of pyretic PGE2 production in Mgll-/- hypothalamus, which was confirmed by lipidomics analysis. Normal blood cytokine responses after LPS administration suggested that MGL-deficiency does not affect pyretic cytokine productions. Diurnal body temperature profiles were normal in Mgll-/- mice, demonstrating that MGL is unrelated to physiological thermoregulation. In conclusion, MGL-dependent hydrolysis of endocannabinoid 2-arachidonoylglycerol is necessary for pyretic PGE2 production in the hypothalamus.
authors.affiliation: Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kenij
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Suzumi M
authors.initials: SM
authors.lastname: Tokuoka
authors.affiliation: Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hamano
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.affiliation: Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005334:Fever / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; C578453:CNR1 protein, mouse; D063388:Endocannabinoids; D005989:Glycerides; C516390:Pla2g4a protein, mouse; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D054513:Group IV Phospholipases A2; D015232:Dinoprostone