Inhibition of peripheral CB ₁ receptors modulates food intake and metabolic efficiency in obesity independently of the gut–brain vagal axis

Background and Purpose Obesity involves profound disruptions in neuronal circuits, neuroendocrine communication and the endocannabinoid system. While global blockade of cannabinoid CB 1 receptors improves metabolism, its clinical use is limited by neuropsychiatric side effects. Peripherally restricted CB 1 receptor antagonists offer a safer alternative, although the neural pathways, specifically the gut–brain vagal axis, mediating their effects remain unclear. Experimental Approach Metabolic and neural effects of peripheral inhibition of CB 1 receptors by JD5037 and AM6545, were assessed in lean and diet‐induced obese (DIO) mice. Metabolic parameters were measured using indirect calorimetry, and neuronal activation was mapped by cFos immunoreactivity. Involvement of vagal signalling was examined using subdiaphragmatic vagotomy (SDV) and antagonists of cholecystokinin and glucagon‐like peptide‐1 (GLP‐1) receptors. Key Results Inhibition of peripheral CB 1 receptors suppressed food intake and shifted nutrient partitioning toward fatty acid oxidation in DIO, but not lean, mice. Obesity up‐regulated CB 1 receptor expression in the nodose ganglia. In DIO mice, peripheral CB 1 receptor inhibition robustly activated satiety‐related brainstem (nucleus tractus solitarius, area postrema, parabrachial nucleus) and hypothalamic (arcuate and paraventricular) nuclei. SDV abolished brainstem activation but failed to blunt hypothalamic recruitment or the anorexigenic and metabolic benefits. Antagonists of cholecystokinin or GLP‐1 receptors did not prevent the feeding‐suppressive effects of JD5037. Conclusions and Implications Our findings revealed a dual‐mechanism model: vagal pathways mediated brainstem engagement, while hypothalamic recruitment and metabolic improvements occurred via vagal‐independent signalling. Thus, peripherally‐restricted CB 1 receptor antagonists indirectly engage central homeostatic circuits, supporting their therapeutic potential for obesity even in conditions with impaired vagal signalling.