Together, these data highlight an important stimulatory effect of CNS but not peripheral leptin on CO2 chemoreception.; While long-term obesity from genetic leptin deficiency causes long-term reductions in CO2 hypercapnic ventilatory responses, whether CO2 sensitivity at the neuronal level, and specifically in 5-HT neurons, is affected due to sustained elevated leptin levels as occurs in obesity remains unknown. Here, LEP is linked to obesity due to melanocortin 4 receptor deficiency.