Abnormal Growth and Feeding Behavior in Upper Airway Obstruction in Rats

Mini Review published: 04 June 2018 doi: 10.3389/fendo.2018.00298 Abnormal Growth and Feeding Behavior in Upper Airway Obstruction in Rats Ariel Tarasiuk1,2* and Yael Segev3 1 Sleep-Wake Disorders Unit, Soroka University Medical Center, Beer-Sheva, Israel, 2 Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel, 3 Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer-Sheva, Israel Edited by: Slava Berger, Johns Hopkins Medicine, United States Reviewed by: Jonathan C. Jun, Johns Hopkins University, United States Zhichao Feng, Albert Einstein College of Medicine, United States *Correspondence: Ariel Tarasiuk Specialty section: This article was submitted to Diabetes, a section of the journal Frontiers in Endocrinology Received: 22 March 2018 Accepted: 18 May 2018 Published: 04 June 2018 Citation: Tarasiuk A and Segev Y (2018) Abnormal Growth and Feeding Behavior in Upper Airway Obstruction in Rats. Front. Endocrinol. 9:298. doi: 10.3389/fendo.2018.00298 Pediatric obstructive sleep apnea (OSA) is a syndrome manifesting with snoring and increased respiratory effort due to increased upper airway resistance. In addition to cause the abnormal sleep, this syndrome has been shown to elicit either growth retardation or metabolic syndrome and obesity. Treating OSA by adenotonsillectomy is usually associated with increased risk for obesity, despite near complete restoration of breathing and sleep. However, the underlying mechanism linking upper airways obstruction (AO) to persistent change in food intake, metabolism, and growth remains unclear. Rodent models have examined the impact of intermittent hypoxia on metabolism. However, an additional defining feature of OSA that is not related to intermittent hypoxia is enhanced respiratory loading leading to increased respiratory effort and abnormal sleep. The focus of this mini review is on recent evidence indicating the persistent abnormalities in endocrine regulation of feeding and growth that are not fully restored by the chronic upper AO removal in rats. Here, we highlight important aspects related to abnormal regulation of metabolism that are not related to intermittent hypoxia per se, in an animal model that mimics many of the clinical features of pediatric OSA. Our evidence from the AO model indicates that obstruction removal may not be sufficient to prevent the post-removal tendency for abnormal growth. Keywords: sleep-disordered breathing, upper airway obstruction, sleep, growth, metabolism, rats INTRODUCTION Obstructive sleep-disordered breathing includes a spectrum of clinical entities with variable severity ranging from primary snoring to obstructive sleep apnea (OSA) (1, 2). Children with OSA suffer from upper airway obstruction (AO) during sleep that is manifested by increased respiratory efforts, large variations in intrathoracic pressure (up to −50 mmHg during peak inspiration), intermittent hypoxia, ultimately leading to sleep fragmentation and nonrestorative sleep. OSA is relatively common in children, and it may have serious consequences on longitudinal growth, body weight, energy metabolism, cardiovascular and neurobehavioral abnormalities, and increased health-care utilization (1–10). Estimates of OSA prevalence range between 1 and 5.7% depending mainly on the populations studied (1, 2, 11, 12). It is estimated that 5–56% of OSA cases develop growth retardation, with the lower prevalence probably reflecting increased awareness and earlier diagnosis and treatment (13–17). The mechanisms underlying the development of growth retardation in OSA continue to be highly controversial. Three Frontiers in Endocrinology | www.frontiersin.org 1 June 2018 | Volume 9 | Article 298 Tarasiuk and Segev Upper AO main possibilities have been put forward to explain growth retardation in OSA. First, it is possible that dysphagia (18) is due to enlarged tonsils and adenoids, and decreased appetite due to changes in olfactory acuity in some cases. Second, it has been postulated that dysregulation of energy supply/ energy expenditure balance (3, 18–20), due to the increased respiratory efforts (work of breathing) during sleep, will lead to increased metabolic expenditure and contribute to slow weight gain in these children (3). 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). GH secretion occurs in pulses from the anterior pituitary somatotropic cells mainly during deep slow wave sleep onset (26, 27). Deep slow wave sleep is initiated in the preoptic area of the hypothalamus and consists of delta electroencephalogram activity, i.e., high-amplitude brain waves with a frequency of oscillation between 0.5 and 4 Hz (23, 28–31). OSA has also been shown to cause growth failure in some young children, and metabolic syndrome and obesity were reported in other cases (1, 3, 5, 6, 13, 15, 16, 18). OSA is most prevalent in 2- to 8-year-old children, when tonsil and adenoid volume is largest relative to the upper airway diameter; these children are usually referred to adenotonsillectomy as the first-line treatment (1, 3, 6, 15, 32). A currently poorly understood phenomenon is the fact that treatment of OSA can lead to accelerated weight gain in children, i.e., it normalizes weight in children who have failure to thrive, but increases the risk for obesity in overweight patients (1, 2, 5, 6, 15, 32–35). Regulation of energy expenditure is multifactorial and includes factors such as metabolic rate at rest, physical activity, and thermic effect of food intake (19, 20, 36, 37). Whole-body energy balance to promote weight gain may be altered following treatment of OSA (19, 20). However, study design and the between-group variability make a conclusion on the effect of treatment difficult. Although adenotonsillectomy in children and positive airway pressure (in adults) treatments predispose humans to a positive energy balance and accelerate body weight gain, sedentary lifestyles, dietary intake, and selection of high caloric/glycemic index foods may have greater impacts on weight change (6, 19, 20, 38–40). However, the majority of clinical studies concentrated on elucidating the endocrine consequences of the surgical treatment while data on normal healthy controls barely exist. Experimental models of sleep apnea provide mechanistic insight into the apnea generation as well as into its impact on cardiovascular, metabolic, and psychological consequences (41, 42). The commonly used model to study OSA involves implementation of intermittent hypoxia, i.e., the repetitive brief hypoxic episodes like those that occur in OSA (43) or specifically dusting sleep (44, 45) to e (...truncated)