Diet-dependent modulation of energy balance by CB1 signaling in peripheral sensory neurons

The endocannabinoid system plays a pivotal role in metabolic regulation, primarily through cannabinoid receptor-1 (CB1) signaling. In this study, we show that rimonabant (Rim), a selective non-restricted CB1 antagonist, induces substantial weight loss across multiple diet groups, although reduced food intake occurred only in the high-fat (HF) diet group. Rim enhanced brown adipose tissue (BAT) thermogenesis across all diets and visceral white adipose tissue (vWAT) thermogenesis in HF and high-carbohydrate (HC) diets. We identified CB1 expression in the gut's splanchnic and vagal neurons and found that CB1 modulation significantly influenced afferent splanchnic but not vagal neuronal activity. Furthermore, selective splanchnic, not vagal, afferent denervation eliminated Rim's anorectic effect. Mice lacking CB1 in sensory neurons (Nav1.8Cre/CB1^flox/flox) showed reduced diet-induced weight gain and diminished metabolic response to JD5037, a peripherally restricted CB1 antagonist. These findings emphasize the importance of CB1 signaling in sensory neurons as a key mechanism regulating energy homeostasis.