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Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis

Molecular Psychiatry volume 27, pages 2340–2354 (2022)Cite this article

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Abstract

The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.

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Fig. 1: Allostatic adaptations of metabolic efficiency to binge eating.
Fig. 2: Binge eating induces dopamine D1R-related molecular modifications.
Fig. 3: Peripheral endocannabinoids (eCBs) govern binge eating.
Fig. 4: The gut-brain vagal axis is required for eCBs-mediated effects.
Fig. 5: Peripheral CB1R signaling modulates dopamine dynamics.
Fig. 6: Peripheral CB1R signaling routed by the vagus nerve controls VTA DA-neurons activity.

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Acknowledgements

We thank Chloé Morel, Rim Hassouna, Anne-Sophie Delbes, Daniela Herrera Moro and Raphaël Denis for technical advice and support; Adrien Paquot (BPBL/UCLouvain) for his help with eCB quantification; Olja Kacanski for administrative support; Isabelle Le Parco, Ludovic Maingault, Angélique Dauvin, Aurélie Djemat, Florianne Michel, Magguy Boa and Daniel Quintas for animals’ care. We acknowledge the technical platform Functional and Physiological Exploration platform (FPE) of the Université de Paris (BFA-UMR 8251) and the animal facility Buffon of the Institut Jacques Monod. This work was supported by the Fyssen Foundation, Nutricia Research Foundation, Allen Foundation Inc., Agence Nationale de la Recherche (ANR-21-CE14-0021-01), Fédération pour la Recherche sur le Cerveau and Association France Parkinson, Université de Paris and CNRS. CB and EM were supported by fellowships from the Fondation pour la Recherche Médicale (FRM). Telemetry experiments were supported by the Continuous Glucose Telemetry Award 2018 (Dr. Denis) and sponsored by Data Sciences International.

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Authors and Affiliations

  1. Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France

    Chloé Berland, Julien Castel, Enrica Montalban, Ewout Foppen, Claire Martin, Serge Luquet & Giuseppe Gangarossa

  2. Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200, Brussels, Belgium

    Romano Terrasi & Giulio G. Muccioli

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  1. Chloé Berland
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Contributions

CB and GG conceived, performed and analyzed most of the experiments. JC performed surgeries and behavioral experiments. EM helped with molecular studies. EF performed vagotomy. CM helped with fiber photometry. GGM and RT analyzed eCB levels. SL provided critical feedback. GG supervised the whole project and wrote the manuscript with contribution from all coauthors.

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Correspondence to Giuseppe Gangarossa.

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Berland, C., Castel, J., Terrasi, R. et al. Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis. Mol Psychiatry 27, 2340–2354 (2022). https://doi.org/10.1038/s41380-021-01428-z

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