Peripheral CB1R inhibition modulates food intake and metabolic efficiency in obesity independently of the gut-brain vagal axis

Obesity arises from profound disruptions in neuroendocrine communication and impaired central regulation of energy homeostasis. The endocannabinoid system (ECS), through cannabinoid type-1 receptors (CB1Rs), is a key modulator of feeding, metabolism, and gut-brain signaling. While global CB1R blockade improves metabolic control, its clinical translation has been limited by adverse neuropsychiatric effects, underscoring the therapeutic potential of peripherally restricted CB1R inhibition whose neural mechanisms remain insufficiently defined. Here, we show that two peripheral CB1R antagonists, the inverse agonist JD-5037 and the neutral antagonist AM6545, selectively suppress food intake and shift nutrient partitioning toward fat oxidation in obese, but not lean, mice, without altering total energy expenditure. We further demonstrate that high-fat exposure markedly upregulates CB1R expression in the nodose ganglia, suggesting an enhanced reliance on periphery-to-brain ECS signaling in obesity. Using cFos mapping, we reveal that inhibition of peripheral CB1Rs robustly recruits satiety-related brainstem and hypothalamic structures. Interestingly, disruption of the gut-brain vagal axis abolishes JD-5037-induced activation of brainstem nuclei but leaves hypothalamic activation, and the anorexigenic response, fully intact. Likewise, pharmacological inhibition of key vagal endocrine mediators, cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), fails to blunt the feeding-suppressive effects of peripheral CB1R blockade. These findings uncover an unprecedent dual mechanism whereby vagal pathways mediate brainstem engagement, whereas hypothalamic recruitment and metabolic benefits arise through vagal-independent signaling. Our results position peripheral CB1R inhibition as a mechanistically distinct approach capable of engaging central homeostatic circuits without direct brain penetration, supporting peripherally acting CB1R antagonists as promising therapeutics for obesity and metabolic disorders.