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

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 integrative 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 food-reward disorders.

Hindbrain catecholaminergic inputs to the paraventricular thalamus scale feeding and metabolic efficiency in stress‐related contexts

“…Indirect calorimetry was performed as described previously (Berland et al., 2022). Mice were monitored for whole energy expenditure (EE), O 2 consumption and CO 2 production, respiratory exchange rate (RER = $${V_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$$/$${V_{{{\rm{O}}_{\rm{2}}}}}$$), fatty acid oxidation (FAO), and locomotor activity using calorimetric cages with bedding, food, and water (Labmaster, TSE Systems GmbH, Bad Homburg, Germany).…”

Progress of neural circuits mechanism underlying metabolic and hedonic feeding

“…Related studies have focused on the influence of a specific brain region on food intake, energy expenditure, and body weight regulation [13,14]. Hedonic feeding is generally associated with dopamine-related neurotransmitters, mainly involving the limbic system of the midbrain, and studies have focused more on the interaction between feeding and the emotional and reward systems [15][16][17][18]. However, there is a growing body of evidence showing that the distinction between these two types of feeding behavior is not particularly clear, suggesting that metabolic and hedonic feeding processes are intertwined and share a large degree of structural and loop similarity and overlap [19][20][21][22].…”