Irreversible metabolic abnormalities following chronic upper airway loading

Abstract

Study Objectives Treatment of obstructive sleep apnea increases obesity risk by an unclear mechanism. Here, we explored the effects of upper airway obstruction and its removal on respiratory homeostasis, energy expenditure, and feeding hormones during the sleep/wake cycle from weaning to adulthood. Methods The tracheas of 22-day-old rats were narrowed, and obstruction removal was performed on post-surgery day 14. Energy expenditure, ventilation, and hormone-regulated feeding were analyzed during 49 days before and after obstruction. Results Energy expenditure increased and body temperature decreased in upper airway obstruction and was only partially recovered in obstruction removal despite normalization of airway resistance. Increased energy expenditure was associated with upregulation of ventilation. Decreased body temperature was associated with decreased brown adipose tissue uncoupling protein 1 level, suppressed energy expenditure response to norepinephrine, and decreased leptin level. Upper airway obstructed animals added less body weight, in spite of an increase in food intake, due to elevated hypothalamic orexin and neuropeptide Y and plasma ghrelin. Animals who underwent obstruction removal fed more due to an increase in hypothalamic neuropeptide Y and plasma ghrelin. Conclusions The need to maintain respiratory homeostasis is associated with persistent abnormal energy metabolism and hormonal regulation of feeding. Surgical treatment per se may not be sufficient to correct energy homeostasis, and endocrine regulation of feeding may have a larger effect on weight change.

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

“…To the best of our knowledge, this study is the first to show that deregulation of energy homeostasis plays an important role in AO-induced growth retardation. Increased energy expenditure in AO is due to upregulation of ventilation in order to maintain respiratory homeostasis 30,44,45 and the extra energy needed for increased additional wakefulness 30 . Orexin participates importantly in maintaining respiratory homeostasis in AO, but it is also responsible for partial sleep loss 29 .…”

“…Insufficient sleep over a long duration can lead to poor bone health that is associated with increased TRAP 5b and decreased osteoblast activity 31 . AO animals increased their caloric intake due to elevation of gut-derived ghrelin, an array of hypothalamic mediator factors, and orexin 30 . Orexin and ghrelin-containing neurons could influence each other, and thereby regulate feeding www.nature.com/scientificreports www.nature.com/scientificreports/ behavior 48 , while short sleep per se also can stimulate gut-derived ghrelin and feeding 49 .…”

“…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.…”

“…Orexins play a role in regulation of feeding, sleep, ventilation 23-26 , and sympathetic activity 27,28 . In the AO animals, enhanced hypothalamic orexin, while important in respiratory homeostasis 29,30 , is also responsible for partial sleep loss and sleep disorder 14,15 . Chronically inadequate sleep in adult rats can adversely affect bone metabolism 31 .…”

“…An increased firing rate of the sympathetic nerves to brown adipose tissue through β-adrenergic receptors increases energy expenditure to generate heat. However, this possibility is unlikely since AO animals do not respond to administration of norepinephrine to generate heat due to decreased brown adipose uncoupling protein 1, leptin level, and lack of available fuel for heat generation 30 .…”