Abstract
The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not yet been investigated. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA→NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA enhanced food-reward seeking and reinforced behaviors, which were associated with increased in vivo DA release dynamics in response to both food- and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which increased energy expenditure and adapted nutrient partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings reveal a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism.
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Acknowledgements
We thank Olja Kacanski for administrative support, Isabelle Le Parco, Aurélie Djemat, Daniel Quintas, Magguy Boa, Ludovic Maingault, Angélique Dauvin and Florianne Michel for animals’ care and genotyping. We thank Dr. Etienne Doumazane for clustering analyses and Dr. Sylvie Robin for the gift of Villin-CreERT2 mice. We acknowledge the technical platform Functional and Physiological Exploration platform (FPE) of the Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, and the animal core facility “Buffon” of the Université Paris Cité/Institut Jacques Monod.
Funding
This work was supported by the Nutricia Research Foundation (#2022-E7), Agence Nationale de la Recherche (ANR-21-CE14-0021-01, ANR-23-CE14-0014-02, ANR-19-CE37-0020-02), Fondation pour la Recherche Médicale (Équipe FRM #EQU202003010155), Fédération pour la Recherche sur le Cerveau and Association France Parkinson, Institut universtaire de France, the Modern Diet and Physiology Research Center (MDPRC), Université Paris Cité, US National Institutes of Health (DA047858), and CNRS. GL is supported by a China Scholarship Council (CSC) fellowship. OO is supported by an FRM fellowship. PDC is recipient of grants from FNRS (FRFS-WELBIO: WELBIO-CR-2022A-02, EOS: program no. 40007505) and La Caixa (NeuroGut). AE is research associate at FNRS and the recipient of grants from FNRS (FRFS-WELBIO: WELBIO-CR-2019S-03R, FNRS: J.0075.22).
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Conceptualization: GG and SL; Investigation: JC, GL, OO, AE, EL, HB, KM, PDC, SL, GG; Formal Data Analysis: JC, SL, GG, HB, KM, AE; Resources: GG, SL, PDC; Funding acquisition: GG, SL, PDC; Supervision: GG and SL; Writing – original draft: GG and SL; Writing – review & editing: all authors.
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PDC and AE are inventors on patent applications dealing with the use of specific bacteria and components in the treatment of different diseases. PDC was co-founder of The Akkermansia Company SA and Enterosys. The other authors declare no competing interests.
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Castel, J., Li, G., Onimus, O. et al. NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02427-6
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DOI: https://doi.org/10.1038/s41380-024-02427-6