NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis.
(2024) Molecular Psychiatry — p. 1-13 (2024)
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- Authors
Castel, Julien 
Onimus, Oriane Gangarossa, Giuseppe
- 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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Citations
Castel, J., Li, G., Onimus, O., Leishman, E., Cani, P., Bradshaw, H., Mackie, K., Everard, A., Luquet, S., & Gangarossa, G. (2024). NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis. Molecular Psychiatry, 1-13. https://doi.org/10.1038/s41380-024-02427-6 (Original work published 2024)