Leptin prevents respiratory depression in obesity

Christopher P. O'Donnell, Charles D. Schaub, Abby S. Haines, Dan E. Berkowitz, Clarke C. Tankersley, Alan R. Schwartz, Philip L. Smith

Research output: Contribution to journalArticlepeer-review

Abstract

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 (Pa(CO2)), 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-Lep(ob) mice, which lack circulating leptin, also exhibit respiratory depression and elevated Pa(CO2) (> 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 μg/d) markedly increased minute ventilation (̇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.

Original languageEnglish (US)
Pages (from-to)1477-1484
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume159
Issue number5 I
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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