Effects of leptin and obesity on the upper airway function

Abstract

Obesity is associated with alterations in upper airway collapsibility during sleep. Obese, leptin-deficient mice demonstrate blunted ventilatory control, leading us to hypothesize that ( 1) obesity and leptin deficiency would predispose to worsening neuromechanical upper airway function and that ( 2) leptin replacement would acutely reverse neuromuscular defects in the absence of weight loss. In age-matched, anesthetized, spontaneously breathing C57BL/6J (BL6) and ob⁻ /ob⁻ mice, we characterized upper airway pressure-flow dynamics during ramp decreases in nasal pressure (P_N) to determine the passive expiratory critical pressure (P_CRIT) and active responses to reductions in P_N, including the percentage of ramps showing inspiratory flow limitation (IFL; frequency), the P_N threshold at which IFL developed, maximum inspiratory airflow (Vi_max), and genioglossus electromyographic (EMG_GG) activity. Elevations in body weight were associated with progressive elevations in P_CRIT (0.1 ± 0.02 cmH₂O/g), independent of mouse strain. P_CRIT was also elevated in ob⁻ /ob⁻ compared with BL6 mice (1.6 ± 0.1 cmH₂O), independent of weight. Both obesity and leptin deficiency were associated with significantly higher IFL frequency and P_N threshold and lower Vi_max. Very obese ob⁻ /ob⁻ mice treated with leptin compared with nontreated mice showed a decrease in IFL frequency (from 63.5 ± 2.9 to 30.0 ± 8.6%) and P_N threshold (from −0.8 ± 1.1 to −5.6 ± 0.8 cmH₂O) and increase in Vi_max (from 354.1 ± 25.3 to 659.0 ± 71.8 μl/s). Nevertheless, passive P_CRIT in leptin-treated mice did not differ significantly from that seen in nontreated ob⁻ /ob⁻ mice. The findings suggest that weight and leptin deficiency produced defects in upper airway neuromechanical control and that leptin reversed defects in active neuromuscular responses acutely without reducing mechanical loads.