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

Amandine Everard, Hubert Plovier, Marialetizia Rastelli, Matthias Van Hul, Alice de Wouters d’Oplinter, Lucie Geurts, Céline Druart, Sylvie Robine, Nathalie M. Delzenne, Giulio G. Muccioli, Willem M. de Vos, Serge Luquet, Nicolas Flamand, Vincenzo Di Marzo and Patrice D. Cani ()
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Amandine Everard: Université catholique de Louvain
Hubert Plovier: Université catholique de Louvain
Marialetizia Rastelli: Université catholique de Louvain
Matthias Van Hul: Université catholique de Louvain
Alice de Wouters d’Oplinter: Université catholique de Louvain
Lucie Geurts: Université catholique de Louvain
Céline Druart: Université catholique de Louvain
Sylvie Robine: Institut Curie, CNRS
Nathalie M. Delzenne: Université catholique de Louvain
Giulio G. Muccioli: UCLouvain, Université catholique de Louvain
Willem M. de Vos: Wageningen University
Serge Luquet: Sorbonne Paris Cité, BFA, UMR8251, CNRS
Nicolas Flamand: Université Laval
Vincenzo Di Marzo: Université Laval
Patrice D. Cani: Université catholique de Louvain

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08051-7

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