Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and the HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 ml min-1 g-1 during normoxia (p < 0.01) and from 3.6 to 4.7 ml min-1 g-1 during hypoxia (p < 0.001), augmenting the HVR from 0.23 ml min-1 g-1/¿FiO2 to 0.31 ml min-1 g-1/¿FiO2 (p < 0.001). The effects of leptin on VE and the HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 ml min-1 g-1 during normoxia (p < 0.05,) and from 2.8 to 3.2 ml min-1 g-1 during hypoxia (p < 0.02), increasing the HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout NREM (20.1 vs.–27.7 ml/min respectively, p < 0.05) and REM sleep (16.5 vs 23.4 ml/min, p < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity. Read more »