The effect of leptin replacement on sleep-disordered breathing in the leptin-deficientob/obmouse

Abstract

Obese leptin-deficient (ob/ob) mice demonstrate defects in upper airway structural and neuromuscular control. We hypothesized that these defects predispose to upper airway obstruction during sleep, and improve with leptin administration. High-fidelity polysomnographic recordings were conducted to characterize sleep and breathing patterns in conscious, unrestrained ob/ob mice (23 wk, 67.2 ± 4.1 g, n = 13). In a parallel-arm crossover study, we compared responses to subcutaneous leptin (1 μg/h) vs. vehicle on respiratory parameters during NREM and REM sleep. Upper airway obstruction was defined by the presence of inspiratory airflow limitation (IFL), as characterized by an early inspiratory plateau in airflow at a maximum level (V̇Imax) with increasing effort. The severity of upper airway obstruction (V̇Imax) was assessed along with minute ventilation (V̇E), tidal volume (VT), respiratory rate (RR), inspiratory duty cycle, and mean inspiratory flow at each time point. IFL occurred more frequently in REM sleep (37.6 ± 0.2% vs. 1.1 ± 0.0% in NREM sleep, P < 0.001), and leptin did not alter its frequency. V̇Imax (3.7 ± 1.1 vs. 2.7 ± 0.8 ml/s, P < 0.001) and V̇E increased (55.4 ± 22.0 vs. 39.8 ± 16.4 ml/min, P < 0.001) with leptin vs. vehicle administration. The increase in V̇E was due to a significant increase in VT (0.20 ± 0.06 vs. 0.16 ± 0.05 ml, P < 0.01) rather than RR. Increases in V̇E were attributable to increases in mean inspiratory flow (2.5 ± 0.8 vs. 1.8 ± 0.6 ml/s, P < 0.001) rather than inspiratory duty cycle. Similar increases in V̇E and its components were observed in non-flow-limited breaths during NREM and REM sleep. These responses suggest that leptin stabilized pharyngeal patency and increased drive to both the upper airway and diaphragm during sleep.

Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response

“…Obstruction was characterized by the development of inspiratory flow limitation as previously described (Pho et al . ). Briefly, the severity of airflow obstruction was defined by maximal inspiratory flow at the onset of flow limitation ( V I max), measured at the point of peak inspiratory airflow.…”

“…EEG and EMG electrodes were implanted with an EEG/EMG Headmount (Pinnacle Technology, Lawrence, KS, USA) as previously described (Pho et al . ). Mice were allowed to recover for 3–4 days prior to polysomnography in a designated room where sleep recordings were later performed.…”

“…Tidal volume and respiratory movements were measured as described above, and EEG/EMG signals were recorded as previously described (Pho et al . ; Fleury Curado et al . ).…”

“…Briefly, the animals were placed in a whole body barometric plethysmography (WBP) chamber (Buxco, Wilmington, NC, USA) with internal diameter of 80 mm, height of 50.5 mm and volume approximately of 0.4 L. The chamber consisted of a sealed animal chamber, a reference chamber and a platform inside the chamber to support the mouse (Pho et al . ). The chamber was equipped with two high‐resistance ports on the upper surface and one large side port and three small side ports at the base.…”

Early improvement in obstructive sleep apnea and increase in orexin levels after bariatric surgery in adolescents and young adults

“…Leptin is a protein synthesized in adipose tissue that increases with advancing obesity. It acts in the hypothalamus to inhibit appetite (18) and is also a respiratory stimulant (19) . There are multiple potential explanations of the decrease in serum leptin so early postoperatively.…”