Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver

Abstract

<b><i>Introduction:</i></b> Previous work suggests the existence of a paracrine signaling mechanism in which histamine released from visceral mast cells into the portal circulation contributes to fasting-induced ketogenesis by stimulating biosynthesis of the endogenous high-affinity PPAR-α agonist oleoylethanolamide (OEA). <b><i>Methods:</i></b> Male C57Bl/6J mice were rendered obese by exposure to a high-fat diet (HFD; 60% fat). We measured histamine, OEA, and other fatty-acid ethanolamides by liquid-chromatography/mass spectrometry, gene transcription by RT-PCR, protein expression by ELISA, neutral lipid accumulation in the liver using Red Oil O and BODIPY staining, and collagen levels using picrosirius red staining. <b><i>Results:</i></b> Long-term exposure to HFD suppressed both fasting-induced histamine release into portal blood and histamine-dependent OEA production in the liver. Additionally, subchronic OEA administration reduced lipid accumulation, inflammatory responses, and fibrosis in the liver of HFD-exposed mice. <b><i>Discussion:</i></b> The results suggest that disruption of histamine-dependent OEA signaling in the liver might contribute to pathology in obesity-associated liver steatosis.