Leptin prevents respiratory depression in obesity

Human obesity leads to an increase in respiratory demands. As obesity becom es more pronounced some individuals are unable to compensate, leading to el evated arterial carbon dioxide levels (Pa-CO2), alveolar hypoventilation, a nd increased cardiorespiratory morbidity and mortality (Pickwickian syndrom e). The mechanisms that link obesity and hypoventilation are unknown, but t hought to involve depression of central respiratory control mechanisms. Her e 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 m ice was investigated. Three days of leptin infusion (30 mu g/d) markedly in creased minute ventilation ((V) over dot E) across all sleep/wake states, b ut particularly during rapid eye movement (REM) sleep when respiration was otherwise profoundly depressed. The effect of leptin was independent of foo d intake, weight, and CO2 production, indicating a reversal of hypoventilat ion by stimulation of central respiratory control centers. Furthermore, lep tin replacement in mutant mice increased CO2 chemosensitivity during non-ra pid 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 d emonstrate in wild-type mice that ventilation is appropriately compensated when obesity is diet-induced and endogenous leptin levels are raised more t han tenfold. These results suggest that leptin can prevent respiratory depr ession 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.