NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis

Abstract

AbstractTheN-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production ofN-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 the 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 been investigated yet. 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 resulted in enhanced food-reward seeking and reinforced behaviors which were associated with increasedin vivoDA 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 led to increased energy expenditure and adapted nutrients partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features.In conclusion, these findings unravel 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.Highlights- NAPE-PLD and NAEs are enriched in the VTA and regulate food-reinforced behaviors and reward processes.- NAPE-PLD scalesin vivoVTA→NAc dopamine dynamics.- NAPE-PLD in the VTA contributes to whole-body energy balance and metabolic efficiency.- Downregulation of VTA NAPE-PLD ameliorates obesity-associated metabolic features.