Intestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis

Amandine Everard,Nicolas Flamand,Serge Luquet,Vincenzo Di Marzo,Marialetizia Rastelli,Giulio G Muccioli,Matthias Van Hul,Hubert Plovier,Sylvie Robine,Patrice D Cani,Willem M De Vos,Lucie Geurts,Nathalie M Delzenne,Alice De Wouters D’Oplinter,Céline Druart

doi:10.1038/s41467-018-08051-7

Abstract

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. Therefore, we generated a mouse model of inducible intestinal epithelial cell (IEC)-specific deletion of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme involved in NAE biosynthesis (Napepld∆IEC). We discovered that Napepld∆IEC mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis. These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. After long-term HFD, Napepld∆IEC mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld∆IEC mice display altered gut microbiota. Akkermansia muciniphila administration partly counteracts the IEC NAPE-PLD deletion effects. In conclusion, intestinal NAPE-PLD is a key sensor in nutritional adaptation to fat intake, gut-to-brain axis and energy homeostasis and thereby constitutes a novel target to tackle obesity and related disorders.

Highlights

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities
As we previously demonstrated that Akkermansia muciniphila, a gut microbe with beneficial effects during obesity, could exert its effects through modulation of intestinal bioactive lipids related to the endocannabinoid system (ECS), we tested whether intestinal NAPE-PLD mediated these effects
Our results show that intestinal Napepld acts as a master sensor for dietary fat in the gut-to-brain axis contributing to the onset of high-fat diet (HFD)-induced metabolic disorders

Summary

Introduction

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. We discovered that NapepldΔIEC mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. Besides increased adipose tissue mass, obesity is associated with chronic inflammation and alterations in most tissues of metabolic relevance. NAE such as oleoylethanolamide (OEA), stearoylethanolamide (SEA), linoleoylethanolamide (LEA) and palmitoylethanolamide (PEA) are structurally close to and share biosynthetic pathways with AEA but do not activate CB1 or CB2 They are considered endocannabinoid-like molecules acting on other receptors such as PPARα or GPR1194,5. NAE degradation is mediated by the activity of the fatty acid amide hydrolase (FAAH) and NAE-hydrolyzing acid amidase (NAAA)[3]

Methods

Results

Conclusion