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  • br Conflict of interest br Acknowledgements This work was

    2022-08-04


    Conflict of interest
    Acknowledgements This work was funded by the University of Turin (ex60% 2014), World Wide Style Project (WWS; University of Turin/Fondazione CRT) and University of Florence (ex60% 2014). ACR and AP designed the study; AP, EB and IO conducted the literature search and analysis; ACR, AP, IO and PLC wrote or contributed to the writing of the manuscript. All co-authors contributed and have approved the submitted version of the paper.
    Introduction After a meal, the absorptive epithelium of the upper small intestine diverts a fraction of the oleic HC-030031 derived from the hydrolysis of dietary lipids toward the production of oleoylethanolamide (OEA) (Schwartz et al., 2008, DiPatrizio and Piomelli, 2015). Acting as a local messenger within the gut, OEA reduces food intake through a mechanism that involves recruitment of peripheral sensory afferents (Rodriguez de Fonseca et al., 2001) and activation of central pathways that utilize oxytocin and histamine as neurotransmitters (Gaetani et al., 2010, Provensi et al., 2014). Several lines of evidence suggest that OEA initiates this response by engaging the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). First, OEA is one of the most potent naturally occurring PPAR-α agonists identified to date (affinity constant, KD, ≈40 nM; median effective concentration, EC50, ≈120 nM) (Fu et al., 2003, Astarita et al., 2006a). Second, the satiety-inducing effects of OEA are abolished by PPAR-α deletion, are mimicked by synthetic PPAR-α agonists, and are associated with increased PPAR-α-regulated transcription in gut mucosa (Fu et al., 2003). Third, viral-mediated enhancement of OEA production in rat jejunum reduces food intake and concomitantly increases local expression of PPAR-α target genes (Fu et al., 2008). Finally, OEA levels in small intestine from various vertebrate species, including fish, snakes, and rodents, rise from ≤50 nM in the fasting state to ≥250 nM after feeding (Astarita et al., 2006b, Fu et al., 2007, Tinoco et al., 2014, Igarashi et al., 2017), a concentration range that is compatible with PPAR-α activation (Fu et al., 2003, Astarita et al., 2006a). In sum, the available data indicate that OEA is a physiologically relevant endogenous agonist for small-intestinal PPAR-α, which participates in the control of satiety (DiPatrizio and Piomelli, 2015). Feeding regulates OEA production also in the liver, but in an opposite direction to that seen in the gut: hepatic OEA levels rise in the fasting state and fall after feeding (Fu et al., 2007, Izzo et al., 2010). The molecular underpinnings and physiological significance of these changes are unknown, but pharmacological evidence hints at a possible role in lipid metabolism. Indeed, subchronic administration of OEA attenuates liver steatosis in obese Zucker rats (Fu et al., 2005) and in a rat model of non-alcoholic fatty liver disease (Li et al., 2015). Moreover, exogenous OEA stimulates fatty-acid oxidation in isolated rat hepatocytes and enhances ketone body production (ketogenesis) in live rats (Guzman et al., 2004). Ketogenesis is an adaptive metabolic response to prolonged nutrient insufficiency, which takes place primarily in liver mitochondria (Grabacka et al., 2016). The process starts with the condensation, catalyzed by Acetyl-CoA acetyltranferase-1 (Acat-1), of two molecules of acetyl-CoA to form acetoacetyl-CoA. Addition of another acetyl-CoA group, mediated by β-Hydroxy-β-methylglutaryl-CoA synthase-2 (Hmgcs-2), yields HMG-CoA, which is then converted into the ketone bodies, acetoacetate and β-hydroxybutyrate (β-OHB). The expression of genes involved in this pathway, including the rate-limiting enzyme Hmgcs-2 (Grabacka et al., 2016), is governed at the transcriptional level by PPAR-α in hepatocytes (Montagner et al., 2016), whose activation in fasting animals is thought to depend primarily on lipolysis-derived fatty acids (Kersten, 2014, Dubois et al., 2017). Here, we describe a paracrine signaling mechanism involved in the control of liver ketogenesis. We show that fasting stimulates extra-hepatic mast cells to secrete histamine, which enters the liver via the portal circulation, activates G protein-coupled H1 receptors, and triggers local biosynthesis of the high-affinity PPAR-α agonist, OEA. Genetic or pharmacological manipulations that disrupt this process do not affect lipolysis, but markedly attenuate fasting-induced ketogenesis, thus revealing a previously unsuspected regulatory role for mast cell-derived histamine and liver OEA production in systemic lipid homeostasis.