Abnormal Growth and Feeding Behavior Persist After Removal of Upper Airway Obstruction in Juvenile Rats

Abstract

Pediatric obstructive sleep-disordered breathing is associated with growth retardation, but also with obesity that has a tendency to persist following treatment. We investigated the effect of upper airways obstruction (AO) and of obstruction removal (OR) in juvenile rats on gut-derived ghrelin and related hypothalamic factors, feeding, and growth hormone (GH) homeostasis. Here, we show that after seven weeks of AO, animals gained less weight compared to controls, despite an increase in food intake due to elevated ghrelin and hypothalamic feeding factors. OR rats who had complete restoration of tracheal diameter, consumed more food due to increased ghrelin and exhibited growth retardation due to deregulation of GH homeostasis. This study is the first to show dysregulation of the hormonal axes controlling feeding behavior and growth that are not fully restored following OR. Thus, surgical treatment by itself may not be sufficient to prevent post-surgical increased food intake and growth retardation.

Abnormal Growth and Feeding Behavior in Upper Airway Obstruction in Rats

“…In the AO model, respiratory load is surgically induced in 22-day-old rats by tracheal narrowing and animals were followed up to 7 weeks; this period is comparable to half a year up to 20 years in humans ( 25 ). AO induces adaptive response in the respiratory system including alterations in respiratory muscles ( 49 , 51 ), control of ventilation ( 52 , 53 ), sleep, growth, and metabolism ( 23 – 25 , 31 , 54 – 57 ).…”

“…However, this mechanism has been disputed, as total energy expenditure was not affected by OSA ( 21 ). Third, more recently, impaired homeostasis of hormones such as growth hormone (GH), ghrelin, and leptin has been reported ( 4 , 5 , 22 – 25 ). The GH homeostasis is recognized as a key mechanism underlying impaired longitudinal growth ( 1 , 4 , 5 ).…”

Upper Airway Obstruction Elicited Energy Imbalance Leads to Growth Retardation that Persists after the Obstruction Removal

“…Surgery. The technique used for sham surgery and to induce AO in juvenile rats was as previously described 14,15,17,47 . During the surgical procedures, the mortality rates in the AO and OR group were less than 10%, and an additional 5% mortality was observed 2-5 days after surgery.…”

“…In the current study, we used a previously described experimental schedule ( Supplementary Fig. S3) 17,30 . On day 14, the AO group was randomized, and OR of the silicon band was performed on half of the animals.…”

“…Increased upper airway resistance in OSA may promote resting energy expenditure by increasing sympathetic activity and/or the increased work of breathing 12,13 .Increased AO in rats mimics many of the features of human OSA such as sleep fragmentation and growth impairment [14][15][16][17] . Sleep plays an important role in normal growth; AO in children and animals leads to sleep disorder that is associated with reduced GH and global and local epiphyseal growth plate (EGP) insulin-like growth factor 1 (IGF 1), resulting in growth retardation 3,14,[17][18][19][20][21][22] . Orexins play a role in regulation of feeding, sleep, ventilation 23-26 , and sympathetic activity 27,28 .…”