Obesity is a complex disease characterized by disruptions in energy homeostasis. Energy intake is governed by many factors, including bidirectional communication between the gastrointestinal tract and the brain via the vagus nerve (Moura-Assis et al., 2021). The gastrointestinal tract provides the brain with information about food intake, such as the macronutrients and volume of food consumed, and thus signals to the brain when to terminate a meal (Moura-Assis et al., 2021). Conversely, the brain regulates digestion and absorption in the gut via vagal efferents (Browning and Travagli, 2011), whose cell bodies are located in the dorsal motor nucleus of the vagus (DMV) in the brainstem. The activity of these neurons is partially governed by central melanocortin-4 receptor (MC4R) signaling, which plays a pivotal role in food intake and energy homeostasis (Yeo et al., 2021). Previous work has demonstrated significant perturbations in gut–brain signaling in obesity, particularly in vagal afferents (de Lartigue, 2016). The extent to which vagal efferent signaling contributes to obesity, however, is understudied.
One way vagal efferents may influence energy intake is by stimulating the production of the endocannabinoid 2-arachidonylglycerol (2-AG). 2-AG is the main ligand of the cannabinoid receptor CB1R, which is highly expressed in the gastrointestinal tract and the vagus, as well as in the CNS. Numerous reports have shown that endocannabinoids influence energy homeostasis, food consumption, and food preference, in part by activating the hypothalamic orexigenic system, which promotes eating. Importantly, there is a positive correlation between plasma endocannabinoid levels and indicators of obesity, such as body mass index and abdominal adiposity (Côté et al., 2007), and levels of key endocannabinoids are elevated in the gut epithelium in obesity (DiPatrizio, 2021). Previous work has shown that vagal CB1Rs regulate gastrointestinal motility, although not body weight (Vianna et …
Correspondence should be addressed to Lauren Jones at lauren.jones{at}ucl.ac.uk.
