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Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis

Abstract : Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepld in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (Napepld(Delta IEC)). After an overnight fast, we exposed wild-type (WT) and Napepld(Delta IEC) mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. Napeple me mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of Napepld(Delta IEC )mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in Napepld(Delta IEC) mice. Following lipid administration, WT and Napepld(Delta IEC) mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP1 receptor (GLP-1R), prevented the hyperphagia of Napepld(Delta IEC) mice upon HFD. We conclude that in response to lipid, Napepld(Delta IEC) mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.
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Submitted on : Tuesday, November 15, 2022 - 1:17:20 PM
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Marialetizia Rastelli, Matthias van Hul, Romano Terrasi, Charlotte Lefort, Marion Regnier, et al.. Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis. AJP - Endocrinology and Metabolism, 2020, 319 (3), pp.E647-E657. ⟨10.1152/ajpendo.00146.2020⟩. ⟨hal-03300410⟩



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