Fever Is Mediated by Conversion of Endocannabinoid 2-Arachidonoylglycerol to Prostaglandin E2

PLoS One. 2015 Jul 21;10(7):e0133663. doi: 10.1371/journal.pone.0133663. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism*
  • Dinoprostone / metabolism*
  • Endocannabinoids / metabolism*
  • Female
  • Fever / metabolism*
  • Glycerides / metabolism*
  • Group IV Phospholipases A2 / genetics
  • Group IV Phospholipases A2 / metabolism
  • Hypothalamus / metabolism
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism*
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism

Substances

  • Arachidonic Acids
  • CNR1 protein, mouse
  • Endocannabinoids
  • Glycerides
  • Pla2g4a protein, mouse
  • Receptor, Cannabinoid, CB1
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Lipoprotein Lipase
  • Group IV Phospholipases A2
  • Dinoprostone

Grants and funding

This work was supported by MEXT KAKENHI Grant Numbers 23790356, 25116707 (to Y.K.), 21220006, 25000015 (to M.K.), and 24229003 (to T.S.), a grant from the Tokyo Society of Medical Sciences, Japan (to Y.K.), and Takeda Science Foundation (to T.S.). Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, is funded in part by Ono Pharmaceutical Co., LTD. (Osaka, Japan) and Shimadzu Corp. (Kyoto, Japan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.