Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling

Objective In visceral obesity, an overactive endocannabinoid/CB₁ receptor (CB₁R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB₁R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB₁R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined. Methods We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037. Results Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY⁺ than with POMC⁺ ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY^−/− mice kept on a high-fat diet. Conclusions Peripheral CB₁R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.