Impact of interrupted leptin pathways on ventilatory control

1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Bloomberg School of Public Health, and 2 Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21224 Submitted 29 August 2003 ; accepted in final form 22 October 2003 Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1 ) leptin deficiency affects the hypoxic ventilatory response and 2 ) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 ± 0.7 vs. 8.9 ± 0.7 ml·min -1 ·%CO 2 -1 , P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep. sleep; obesity hypoventilation; melanocortin receptor; neuropeptide Y Address for reprint requests and other correspondence: V. Y. Polotsky, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: vpolots1{at}jhmi.edu ).