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

Marialetizia Rastelli,Charlotte Lefort,Matthias Van Hul,Rubén Nogueiras,Marion Régnier,Nathalie M Delzenne,Patrice D Cani,Giulio G Muccioli,Serge Luquet,Romano Terrasi,Daniel Beiroa,Amandine Everard

doi:10.1152/ajpendo.00146.2020

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 (NapepldΔIEC). After an overnight fast, we exposed wild-type (WT) and NapepldΔIEC 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. NapepldΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of NapepldΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in NapepldΔIEC mice. Following lipid administration, WT and NapepldΔIEC 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 GLP-1 receptor (GLP-1R), prevented the hyperphagia of NapepldΔIEC mice upon HFD. We conclude that in response to lipid, NapepldΔIEC 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.

Highlights

Feeding and energy homeostasis are essential life processes that every living organism must attain to survive
After confirming that NapepldDIEC mice ate significantly more in comparison with WT mice following 4 h of HFD exposure (Fig. 1A), we explored the mechanisms potentially involved in this behavior
In response to HFD, hypothalamic OEA levels were decreased by $55% in NapepldDIEC mice (Fig. 1C). These data strongly suggested an altered regulation of the orexigenic AEA and the anorexigenic OEA in response to HFD exposure in the hypothalamus of NapepldDIEC mice compared with WT mice

Summary

Introduction

Feeding and energy homeostasis are essential life processes that every living organism must attain to survive. Among the different regulatory pathways involved, the endocannabinoid system (ECS) functions as a potent regulator of feeding behavior and energy balance. The ECS is composed of bioactive lipid mediators, their membrane-associated and nuclear receptors, and enzymes involved in the synthesis and degradation of these mediators [45]. N-acylethanolamines (NAEs) are a subgroup of bioactive lipids belonging to the ECS that share structural similarities having a common ethanolamide moiety linked to a specific fatty acid. The levels of NAEs are tightly regulated by ondemand synthesis from membrane phospholipids and rapid degradation [30]. N-acylphosphatidyletanolamine phospholipase D (NAPE-PLD) is considered the main synthetizing enzyme for NAEs, studies using total Napepld knockout (NAPE-PLDÀ/À) mice have suggested the existence of alternative pathways [29]. Hydrolysis of NAEs is mediated by fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) [33, 50]

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