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.