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

Background and PurposeObesity involves profound disruptions in neuronal circuits, neuroendocrine communication and the endocannabinoid system (ECS). While global cannabinoid type-1 receptor (CB1R) blockade improves metabolism, its clinical use is limited by neuropsychiatric side effects. Peripherally restricted CB1R antagonists offer a safer alternative, yet the neural pathways, specifically the role of the gut-brain vagal axis, mediating their effects remain unclear. Experimental ApproachWe investigated the metabolic and neural effects of peripheral inhibition of CB1R (JD5037 and AM6545) in lean and diet-induced obese (DIO). Metabolic parameters were assessed using indirect calorimetry, and neuronal activation was mapped by cFos immunoreactivity. The requirement for vagal signaling was examined using subdiaphragmatic vagotomy (SDV) and pharmacological blockade of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) receptors. Key ResultsPeripheral CB1R inhibition suppressed food intake and shifted nutrient partitioning toward fatty acid oxidation in DIO, but not lean, mice. Obesity upregulated CB1R expression in the nodose ganglia. In DIO mice, peripheral CB1R inhibition robustly activated satiety-related brainstem (NTS, AP, PBN) and hypothalamic (ARC, PVN) nuclei. SDV abolished brainstem activation but failed to blunt hypothalamic recruitment or the anorexigenic and metabolic benefits. Furthermore, antagonism of CCK or GLP-1 receptors did not prevent the feeding-suppressive effects of JD5037. Conclusions and ImplicationsOur findings reveal a dual-mechanism model: vagal pathways mediate brainstem engagement, while hypothalamic recruitment and metabolic improvements occur via vagal-independent signaling. These results demonstrate that peripherally restricted CB1R antagonists indirectly engage central homeostatic circuits, supporting their therapeutic potential for obesity even in conditions with impaired vagal signaling. Bullet point summaryO_ST_ABS What is already knownC_ST_ABSO_LIObesity is associated with elevated circulating endocannabinoids, reflecting chronic overactivation of the peripheral endocannabinoid system. C_LIO_LIClinical and preclinical studies indicate that peripheral CB1R inhibition ameliorates obesity-related dysfunctions. C_LI What this study addsO_LIPeripheral CB1R inhibition suppresses food intake and promotes fatty acid oxidation in obese but not lean conditions. C_LIO_LIPeripheral CB1R inhibition engages brainstem nuclei via vagal signaling and hypothalamic nuclei via vagal-independent mechanisms. C_LI Clinical significanceO_LIMetabolic state-dependent CB1R responsiveness must be considered when designing endocannabinoids-targeted obesity therapies. C_LIO_LIPeripheral CB1R antagonists engage central homeostatic circuits via body-brain pathways, warranting surveillance of CNS outcomes. C_LI