Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-08051-7
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Funding
- FNRS
- FRSM (Fonds de la recherche scientifique medicale, Belgium) [J.0084.15, 3.4579.11]
- Projet de Recherche [T.0138.14]
- Action de Recherche Concertee (Communaute francaise de Belgique) [12/17-047]
- Social Sciences and Humanities Research Council (SSHRC)
- Natural Sciences and Engineering Research Council (NSERC)
- Canadian Institutes of Health Research (CIHR)
- FRFSWELBIO [WELBIO-CGR-2017C-02]
- Funds Baillet Latour (Grant for Medical Research 2015)
- ERC Starting Grant 2013 (European Research Council) [336452-ENIGMO]
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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(Delta IEC)). We discovered that Napepld(Delta 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(Delta IEC) mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld(Delta 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.
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