Impact of interrupted leptin pathways on ventilatory control.
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 x min(-1) x %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.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21224, USA. vpolots1@jhmi.edu
Vsevolod Y
VY
Polotsky
Marc C
MC
Smaldone
Matthew T
MT
Scharf
Jianguo
J
Li
Clarke G
CG
Tankersley
Philip L
PL
Smith
Alan R
AR
Schwartz
Christopher P
CP
O'Donnell
D000818:Animals; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D012123:Pulmonary Ventilation / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012890:Sleep / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D014851:Wakefulness / Q000235:genetics / Q000502:physiology
D020738:Leptin