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

<div><p>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 (<i>Mgll</i>^−/−) mice, CB1 receptor-MGL compound-deficient (<i>Cnr1</i>^−/−<i>Mgll</i>^−/−) mice, cytosolic phospholipase A₂α (cPLA₂α)-deficient (<i>Pla2g4a</i>^−/−) mice, and diacylglycerol lipase α (DGLα)-deficient (<i>Dagla</i>^−/−) mice. Febrile reactions were abolished in <i>Mgll</i>^−/− and <i>Cnr1</i>^−/−<i>Mgll</i>^−/− mice, whereas <i>Cnr1</i>^−/−<i>Mgll</i>^+/+, <i>Pla2g4a</i>^−/− and <i>Dagla</i>^−/− 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 <i>Mgll</i>^−/− and wild-type control mice, suggesting a lack of pyretic PGE₂ production in <i>Mgll</i>^−/− 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 <i>Mgll</i>^−/− 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.</p>