Human
obesity leads to an increase in respiratory demands. As
obesity becomes more pronounced some individuals are unable to compensate, leading to elevated arterial
carbon dioxide levels (PaCO2), alveolar
hypoventilation, and increased cardiorespiratory morbidity and mortality (
Pickwickian syndrome). The mechanisms that link
obesity and
hypoventilation are unknown, but thought to involve depression of central respiratory control mechanisms. Here we report that obese C57BL/6J-Lepob mice, which lack circulating
leptin, also exhibit
respiratory depression and elevated PaCO2 (> 10 mm Hg; p < 0. 0001). A role for
leptin in restoring ventilation in these obese, mutant mice was investigated. Three days of
leptin infusion (30 microg/d) markedly increased minute ventilation (V E) across all sleep/wake states, but particularly during rapid eye movement (REM) sleep when respiration was otherwise profoundly depressed. The effect of
leptin was independent of food intake, weight, and CO2 production, indicating a reversal of
hypoventilation by stimulation of central respiratory control centers. Furthermore,
leptin replacement in mutant mice increased CO2 chemosensitivity during non-rapid eye movement (NREM) (4.0 +/- 0.5 to 5.6 +/- 0.4 ml/min/%CO2; p < 0.01) and REM (-0.1 +/- 0.5 to 3.0 +/- 0.8 ml/min/%CO2; p < 0.01) sleep. We also demonstrate in wild-type mice that ventilation is appropriately compensated when
obesity is diet-induced and endogenous
leptin levels are raised more than tenfold. These results suggest that
leptin can prevent
respiratory depression in
obesity, but a deficiency in central nervous system (CNS)
leptin levels or activity may induce
hypoventilation and the
Pickwickian syndrome in some obese subjects. O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL.
Leptin prevents
respiratory depression in
obesity.