Rola adipokin w obturacyjnym bezdechu podczas snu This copy is
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Rola adipokin w obturacyjnym bezdechu podczas snu This copy is
artykuł przeglądowy / review article Role of adipokines in obstructive sleep apnea syndrome Rola adipokin w obturacyjnym bezdechu podczas snu Śmietanowska Maryla1, Balcerzak Jarosław2, Cudnoch-Jędrzejewska Agnieszka1, Wysocki Jarosław3, Niemczyk Kazimierz2 Department of Experimental and Clinical Physiology, Center for Preclinical Research Laboratory, Medical University of Warsaw, Poland Department of Otolaryngology, Medical University of Warsaw 3 Department of Health Sciences, Faculty of Natural Sciences, Siedlce University of Natural Sciences and Humanities 1 2 Article history: Received: 20.04.2015 Accepted: 20.04.2015 Published: 30.06.2015 ABSTRACT: bstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized by repetitive episodes of apnea/ O hypopnea due to ventilatory limitation or arrest. A number of risk factors of OSAS were identified, with obesity being one of the most principal ones. However, the reason why sleep apnea episodes occur in so many obese patients remains unknown. The limited literature data available suggest a possibility of increased secretion of certain adipokines such as leptin or apelin within the adipose tissue in response to hypoxia. Literature includes a number of reports on the role of individual adipokines in OSAS. However, no article has been published to date to summarize the results of these studies. This article discusses the results of studies on the role of leptin, apelin, omentin, obestatin, ghrelin, resistin and visfatin in OSAS. Particular attention was paid to studies assessing diurnal profiles of adipokine secretion and the effects of continuous positive air pressure (CPAP) treatment on the changes in adipokine plasma levels were described. The analysis of studies conducted to date prevents unambiguous assessment of whether the change in the plasma levels of individual adipokines is a direct consequence of hypoxia due to OSAS or rather of the activity of the adipose tissue being excessively developed in most OSAS patients. KEYWORDS: Adipokines, OSAS, CPAP, Apelin, Leptin, Ghrelin, Obestatin, Omentin, Resistin, Visfatin ABBREVIATIONS:OSAS – Obstructive Sleep Apnea Syndrome, AHI – Apnea-Hypopnea Index, CPAP – Continuous Positive Airway Pressure, NTS – Nucleus Tractus Solitarii, RVLM – Rostral Ventrolateral Medulla, BMI – Body Mass Index, UPPP – Uvulopalatopharyngoplasty, AP – Apelin, RELM/FIZZ – Resistin-Like Molecules Found in the Inflammatory Zone, NREM – NonRapid Eye Movement, G/O ratio – Ghrelin/Obestatin Ratio STRESZCZENIE: Obturacyjny bezdech podczas snu (OBPS, ang. obstructive sleep apnea syndrome, OSAS) jest zaburzeniem snu, w którym występują powtarzające się, wywołane ograniczeniem lub zatrzymaniem wentylacji epizody anoksemiczno-hipoksemiczne. Wyróżniono wiele czynników ryzyka w zespole snu z bezdechem śródsennym, pośród których jednym z głównych jest otyłość. Nie jest jednak jasne, dlaczego u tak wielu chorych z otyłością występują bezdechy nocne. Nieliczne dane z piśmiennictwa wskazują na możliwość wzrostu sekrecji przez tkankę tłuszczową niektórych adipokin, takich jak leptyna i apelina, w odpowiedzi na hipoksję. W piśmiennictwie jest wiele doniesień dotyczących roli poszczególnych adipokin w OBPS, brakuje jednak pracy, która stanowiłaby podsumowanie powyższych badań. W artykule zostały omówione wyniki badań dotyczące roli leptyny, apeliny, omentyny, obestatyny, greliny, rezystyny i wisfatyny w OBPS. Szczególną uwagę zwrócono na prace, w których badano dobowy profil wydzielania adipokin oraz opisano wpływ terapii dodatnim ciśnieniem w drogach oddechowych (CPAP) na zmiany ich stężenia w osoczu. Na podstawie analizy dotychczasowych badań nie można jednoznacznie określić, czy zmiana stężenia poszczególnych adipokin w osoczu stanowi efekt samego niedotlenienia towarzyszącego OBPS, czy aktywności tkanki tłuszczowej, nadmiernie rozwiniętej u większości osób z OBPS. SŁOWA KLUCZOWE:Adipokins, OSAS, CPAP, apelin, leptin, ghrelin, obestatin, omentin, rezistin, visfatin POLSKI PRZEGLĄD OTORYNOLARYNGOLOGICZNY, TOM 4, NR 2 (2015), s. 27-33 DOI:10.5604/20845308.1151456 27 artykuł przeglądowy / review article SKRÓTY: OSAS – zespół bezdechu podczas snu, AHI – wskaźnik bezdechów i spłyceń oddechu, CPAP – stałe dodatnie ciśnienie w drogach, ddechowych, NTS – jądro pasma samotnego, RVLM – dogłowowy brzuszno-boczny obszar rdzenia przełużonego, BMI – wskaźnik masy ciała, UPPP – uwulopalatofaryngoplastyka, AP – apelina, ReLM/FIZZ – molekuły rezystyno-podobne, obecne w miejscu stanu zapalnego, NReM – sen wolnofalowy, G/O ratio – stosunek grelina/obestatyna INTRODUCTION Obstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized by cyclically repetitive episodes of apnea and hypopnea. Both apnea and hypopnea lead to hypoxemia and then to hypoxia that disturbs the function and initiates pathological changes in the tissues of virtually all internal organs. Obesity has been for a long time considered one of the principal risk factors of OSAS. However, not all causal relationships between both factors have been unambiguously identified to date. It is believed that the adipose tissue mass contributes to limited ventilation not only by mechanical reduction in the mobility of diaphragm and narrowing of the airway lumen at the neck level (parapharyngeal, palatal, glossal deposits) [Mortimore et al. 1998, Resta et al. 2003], but also by chemical interaction with upper respiratory tract muscles [Vgontzas 2008]. Increased levels of biologically active substances secreted by the adipose tissue, including adipokines, are measured in the blood of obese patients. Reports were also published with regard to the possibility of increased secretion of certain adipokines such as leptin or apelin in response to hypoxia due to OSAS. In some articles on the subject, the authors paid special attention to the effect of OSAS-related chronic hypoxia on the diurnal rhythm of secretion of adipokines (Arnardottir 2009; Sanchez-de-la-Torre 2014). Literature data also suggest a possible relationship between sleep deprivation and metabolic disorders. Changes in the levels of hormones regulating the course of metabolic processes such as ghrelin or leptin were observed in subjects working at different times of the day (Mota et al. 2014). Polysomnographic examinations are a gold standard in the diagnostics of OSAS (Epstein LJ, 2009). However, they are expensive and require the presence of a trained personnel. Therefore, research is under way on novel, less expensive diagnostic methods that would facilitate screening of large populations of potential OSAS patients. The literature contains a large number of reports on the role of individual adipokines in OSAS. However, no article has been published to date to summarize the results of these studies. 28 THE ROLE OF SELECTED ADIPOKINES IN OSAS Leptin Leptin is an adipokine that reduces the feeling of hunger due to its ability to stimulate the satiety center within the hypothalamus (Zhang et al., 1994). It also reduces glucogenesis, production of glycogen and pancreatic secretion of insulin. The plasma level of leptin may be considered an indirect indicator of systemic energy supply. It has been known for many years that the blood levels of leptin are strictly related to the quantity of adipose tissue in both humans and animals. Elevated plasma leptin levels are observed mainly in pathological conditions related to excessive accumulation of adipose tissue (simple obesity, Cushing’s syndrome) while reduced leptin levels are observed upon reduction of fatty reserve (anorexia nervosa) (Ziora 2010, Meier 2004). Increased leptin levels in the blood of obese patients are often accompanied by reduced leptin sensitivity of peripheral tissues referred to as leptin resistance (Fitzpatrick et al. 1998). As also suggested by literature data, leptin is involved in the pathogenesis of OSAS. As shown by Geiger (2011), expression of the leptin gene increased in hypoxic conditions within isolated adipocytes. On the other hand, O’Donnell et al. (1999), using a murine model of obesity with leptin insufficiency observed that an increased supply of leptin led to reduction in the number of hypoventilation episodes. Other studies conducted in rats revealed that leptin regulates chemoreceptor-mediated reflexes by modulating the response of the nucleus tractus solitarii NTS) neurons, possibly explaining the observed increase in sympathetic activity and arterial blood pressure upon chronic periodic hypoxia (Ciriello et al. 2012). Phillips et al. (2000) reported significantly higher leptin levels in the plasma of obese OSAS patients as compared to patients with normal BMI values. Two years later, the same group of researchers, based on the results of studies conducted in obesity-hypoventilation syndrome patients proposed a hypothesis of leptin involvement in the control of the alveolar ventilation WWW.OTORHINOLARYNGOLOGYPL.COM artykuł przeglądowy / review article process. Numerous studies seem to confirm the positive correlation between plasma leptin levels and the apnea-hypopnea index (AHI) in OSAS patients (Ulukavak et al. 2005, Tokuda et al. 2008, Lin et al. 2014). It seems that elevated leptin levels in OSAS patients might be to a certain degree independent of the obesity: Ulukavak et al. (2005) and Kapusuz et al. (2014) observed that leptin levels in obese OSAS patients were higher than leptin levels in obese patients without OSAS burden. Results of these studies were contradicted by the results obtained by Ursavas et al. (2010) and Sanchez et al. (2012, 2014) who observed no changes or relationships between plasma leptin levels and OSAS, thus suggesting that leptin levels are correlated with obesity rather than OSAS itself. In none of his studies was Sanchez able to observe any differences in plasma leptin levels in obese and non-obese patients, either in OSAS patients or in the control group. In addition, no changes in the diurnal plasma profile of leptin were observed in OSAS patients (Sanchez et al. 2014). Ursavas et al. (2010) observed no relationship between blood leptin levels and AHI values, while a positive correlation with BMI values was observed. However, in the recent years, many authors described a significant drop in plasma leptin levels in patients treated by continuous positive air pressure CPAP) despite constant body weight being maintained in those patients (Ip et al. 2000, Harsch et al. 2003, Nakra et al. 2008, Zirik et al. 2011). On the other hand, Garcia et al. (2011) observed no changes in plasma leptin levels during a 6-month CPAP treatment of patients in their study group. Sanchez et al. (2012) demonstrated the effect of CPAP on the reduction in leptin levels only in obese OSAS patients. While studying the effects of other forms of OSAS treatment on blood leptin levels, Lin et al. (2014) observed that leptin levels were normalized after uvulopalatopharyngoplasty (UPPP) resulting in the reduction in the number of apnea episodes. Apelin Apelin (AP) is an adipokine, a ligand of the APJ receptor, responsible e.g. for regulation of the cardiovascular function and carbohydrate metabolism, including reduction of blood glucose levels. Apelin also appears to play an important role in regulation of responses to hypoxia. Seyedabadi et al. (2002) used a rat model to demonstrate that administration of apelin to NTS led to reduction in the POLSKI PRZEGLĄD OTORYNOLARYNGOLOGICZNY, TOM 4, NR 2 (2015), s. 27-33 amplitude of phrenic nerve discharges and, in some cases, even to apnea. In contrast, administration of apelin to rostral ventrolateral medulla (RVLM), led to an increase in the amplitude of phrenic nerve discharges. Eyers et al. (2008) demonstrated the effect of hypoxia on the increase in apelin expression in isolated colonies of mouse epithelial cells, smooth muscle cells and mouse lung tissue fragments. Geiger et al. (2011) observed increased expression and secretion of apelin in isolated human adipocytes in reduced oxygen supply conditions. This allows to assume that hypoxia observed in the course of OSAS may be a factor stimulating apelin secretion. Boucher et al. (2005) reported increased plasma apelin levels in obese patients as compared to individuals with a normal body mass. The apelin levels were subject to significant reduction following body weight loss. Apelin levels were shown to increase as a result of insulin secretion. OSAS patients often present with obesity and insulin resistance. It is possible that the increase in blood apelin levels in OSAS patients is due not only to nocturnal hypoxia, but also to the continuously elevated insulin levels as a result of insulin resistance. Boucher suggested that the increase in blood apelin levels was due to the increase in insulin resistance rather than to obesity itself. Henley et al. (2009) performed 24-hour measurements of blood apelin levels in obese patients (BMI>30) with newly diagnosed OSAS as well as after 3 months of CPAP treatment. Fasting plasma apelin levels were significantly higher before the treatment as compared to the results obtained after 3 months of CPAP therapy. However, the authors observed no variability in 24-hour apelin secretion before CPAP treatment while after the treatment, maximum plasma levels of apelin were observed at 6:00 pm and minimum plasma levels were observed between 10:00 pm and 2:00 am, possibly suggesting that CPAP restored the diurnal rhythm of apelin secretion. No relationship was demonstrated between the fasting plasma apelin levels and BMI in patients with untreated OSAS. On the other hand, apelin levels were negatively correlated with BMI values following the CPAP treatment. Henley et al. (2009) proposed that the elevated apelin levels in obese patients with OSAS and insulin resistance might counteract increased blood glucose levels. The authors demonstrated that after CPAP treatment, mean apelin levels were reduced during oral glucose tolerance tests (OGTT), perhaps due to down-regulation of insulin receptors as the result of improved insulin sensitivity of peripheral tissues. On the other hand, Zirik et al. (2011) observed no reduction in apelin levels in obese OSAS patients (BMI>30) following three months of CPAP treatment. However, they managed to confirm the existence of correlations between plasma AP levels and posttreatment BMI and AHI values. 29 artykuł przeglądowy / review article Adiponectin Adiponectin is an adipokine affecting mainly the metabolism of carbohydrates and fatty acids as well as increasing the insulin resistance of peripheral tissues (Ouchi et al, 1999). In the study conducted by Geiger (2011) in isolated human adipocytes in hypoxic conditions, expression of adiponectin was reduced, in contrast to apelin and leptin. Kanbay et al. (2008) demonstrated that plasma adiponectin levels are significantly lower in obese OSAS patients as compared to obese subjects without OSAS. Similar results were obtained by Zhang et al. (2006) and Vatansever et al. (2011). Based on the positive correlation between plasma adiponectin levels and AHI and BMI values, the researchers suggested that reduced adiponectin levels were related to OSAS and independent from obesity. Yoshikawa et al. (2014) observed increased plasma adiponectin levels following three months of CPAP treatment not accompanied by change in BMI values. Kosacka et al. (2013) and Sanchez-de-la-Torre et al. (2012) were unable to confirm these results. They observed no relationship between AHI and blood adiponectin levels. Kosacka et al. (2013) observed reduction in blood adiponectin levels only in OSAS patients with concomitant type II diabetes. Results of these studies indicate that adiponectin levels are correlated with obesity itself or insulin resistance rather than OSAS. At the same time, three months of CPAP treatment significantly reduced plasma adiponectin levels in all OSAS patients regardless of their BMI values. Omentin Omentin is an adipokine produced by subadipose tissue rather than by adipocytes. Omentin regulates the metabolism of carbohydrates by means of increasing insulin resistance and glucose consumption in peripheral tissues. Therefore, omentin secretion is reduced in obesity (De Souza Batista, 2007) and increased upon food deprivation (Moreno-Navarrete, 2010). Zirlik et al. (2013) assessed the diurnal profile of omentin secretion in obese OSAS patients (BMI>30) and in the control group (mean BMI of 26.7, no OSAS). Nocturnal drop in omentin levels was observed in the control group. Three months of CPAP led to partial normalization of omentin levels in the morning hours. Wang et al. (2013) demonstrated significantly higher plasma omentin levels in OSAS patients as compared to healthy subjects. Correlation between omentin and AHI was positive while correlation between omentin and VMI was negative. Kurt et al. (2014). (2014) demonstrated significantly 30 higher, BMI-independent blood omentin in all subgroups of OSAS patients as compared to the control group. At the same time, plasma omentin levels in patients with high AHI values (AHI>30) was significantly lower than in the remaining groups. However, no relationship was demonstrated between blood omentin levels and the BMI or AHI values. Ghrelin Ghrelin and obestatin are synthesized from the same protein called preproghrelin. Ghrelin had been initially discovered as a growth hormone (GH) receptor ligand. It was confirmed to be involved in the hunger and satiety center and body weight regulation (Wren 2002). Szentirmai et al. (2006) reported that intrahypothalamic administration of ghrelin to rats led to promotion of wakefulness, suppression of NREM sleep and provided a strong stimulus to food intake. Schwenke et al. (2010) analyzed the effects of exogenous ghrelin in the rat model of chronic hypoxia as well as the effect of ghrelin on the ventilatory response to acute hypoxia. No evidence was found to support any significant changes in the basic respiratory drive being caused by ghrelin administration. The only finding was exacerbation of response to acute hypoxia as observed in chronic hypoxia. Plasma levels of ghrelin in obese subjects were significantly lower than in lean subjects (Tschop M, 2001), as also confirmed by Itoh et al. (2004) who observed increased ghrelin levels in patients with BMI<20. Harsch et al. (2003) demonstrated that ghrelin levels in OSAS patients were significantly higher than in control subjects with similar BMI values. Ursavas et al. (2010) demonstrated a relationship between ghrelin levels and clinical intensity of OSAS as reflected by AHI values. Results of these studies were contradicted by the results obtained by Ursavas et al. (2005) who observed no difference in plasma ghrelin levels in obese OSAS patients as compared to the control group (non-obese, non-OSAS subjects). Liu et al. (2014) demonstrated that only the ghrelin/obestatin ratio (G/O ratio) was negatively correlated with AHI, while the only negative correlation of plasma ghrelin levels was that with BMI. In 2014, the newest study by Sanchez et al. was published to report no significant differences in the diurnal profiles of ghrelin secretion in obese patients and the control group. In the study by Harsch et al. (2003) ghrelin levels were significantly reduced as compared to baseline values after as little as two days of CPAP treatment. The fact that changes in the WWW.OTORHINOLARYNGOLOGYPL.COM artykuł przeglądowy / review article levels of this adipokine are observed so early after initiation of treatment may support the hypothesis that ghrelin levels are dependent not only on the obesity and distribution of adipose tissue but also on other factors such as repeating episodes of hypoxia or hypercapnia. Takahashi et al. (2008) described only the effect of CPAP on the levels of acylated ghrelin characterized by higher biological activity. On the other hand, Sanchez et al. (2012) demonstrated no effects of three-month CPAP treatment on plasma levels of ghrelin in OSAS patients. Obestatin The function of obestatin is opposite to that of ghrelin. It inhibits the activity of hunger center and insulin secretion. Peripheral administration of obestatin reduced body mass increase in rats (Zhang et al. 2005). Meanwhile, central administration of obestatin in rats had a sleep-promoting effect (in contrast to ghrelin), including the NREM phase which might be partially a result of behavioral manifestation of satiety (Szentirmai et al. 2006). Zirik et al. (2011) reported significantly lower levels of obestatin in obese OSAS patients as compared to the control group. In addition, no effect of the three months of CPAP treatment on the plasma obestatin levels could be observed. On the other hand, Liu et al. (2014) demonstrated no differences in plasma obestatin levels between obese or overweight patients as compared to the control group. The ghrelin/obestatin ratio was significantly lower in obese patients as compared to the control group with similar BMI, albeit only in OSAS patients. This suggests that obestatin levels are correlated with obesity rather than OSAS. Resistin Resistin is an adipokine produced mainly in mononuclear cells (macrophages) of adipose tissue (Filkova et al. 2013). Resistin belongs to the family of resistin-like molecules found in the inflammatory zone (RELM/FIZZ). Resistin mRNA levels are reduced upon food deprivation and increase after administration of food. Steppann et al. (2001) observed increased plasma resistin levels in murine models of both genetic and high-fat diet-induced obesity. Intraperitoneal administration or resistin in mice led to disturbed glucose homeostasis. In addition, POLSKI PRZEGLĄD OTORYNOLARYNGOLOGICZNY, TOM 4, NR 2 (2015), s. 27-33 administration of anti-resistin antibodies to mice with highfat diet-induced obesity improved insulin sensitivity of peripheral tissues. Harsh et al. (2004) observed no changes in plasma resistin levels after two days and two months of CPAP treatment in OSAS patients (BMI>25). At the same time, negative correlation was observed between plasma resistin levels and insulin sensitivity index (ISI) values. Absence of changes in plasma resistin levels upon CPAP treatment was confirmed several years later by Garcia et al. (2011). Ursavas et al. (2010) demonstrated no differences in resistin levels between OSAS patients and non-OSAS subjects with similar BMI values (BMI>30). Plasma resistin levels were reported to be correlated with plasma leptin levels. Visfatin Visfatin is an adipokine that enhances insulin resistance and cellular glucose uptake. Plasma visfatin levels are increased in overweight/obese individuals, patients with type II diabetes or metabolic syndrome (Chang et al. 2011). The study by Trakada et al. (2009) compared visfatin levels in OSAS patients and healthy subjects (BMI of >30 in both groups). No relationships were observed between blood visfatin levels and AHI or BMI values. Summary The presented results of studies on plasma concentrations of selected adipokines in OSAS patients do not allow for unambiguous conclusions to be drawn. 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Cite this article as: Śmietanowska M., Balcerzak J., Cudnoch-Jędrzejewska A., Wysocki J., Niemczyk K.: Role of adipokines in obstructive sleep apnea syndrome. Pol Otorhino Rev 2015; 4(2): 27-33 POLSKI PRZEGLĄD OTORYNOLARYNGOLOGICZNY, TOM 4, NR 2 (2015), s. 27-33 33