Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Biological plausibility linking sleep apnoea and metabolic dysfunction

Nature Reviews Endocrinology volume 12, pages 290–298 (2016)Cite this article

Subjects

Key Points

  • Obstructive sleep apnoea (OSA) is a very common disorder in the general population, and 50–65% of adult and pediatric patients with OSA are obese

  • Intermittent hypoxaemia during sleep and fragmentation of sleep architecture are the two major constitutive perturbations that characterize OSA

  • In epidemiological studies, OSA is independently associated with metabolic comorbidities, such as the metabolic syndrome, fatty liver disease, adipose tissue dysfunction, insulin resistance and atherosclerosis, particularly when obesity is concurrently present

  • Despite divergent phenotypic effects on adipose tissue, both intermittent hypoxaemia during sleep and sleep fragmentation have been mechanistically linked to altered metabolic phenotypes in preclinical studies performed in rodent models

  • Systemic and organ-specific inflammation, oxidative stress and autonomic nervous system imbalance probably contribute to OSA-associated metabolic dysfunction; other mechanisms, including gut microbiota dysbiosis and endoplasmic reticulum stress, are under investigation

  • Interventional trials in which patients with OSA were effectively treated reveal variable subsequent improvements in metabolic morbidity, which suggests complex interactions between alterations in sleep and oxygenation and obesity

Abstract

Obstructive sleep apnoea (OSA) is a very common disorder that affects 10–25% of the general population. In the past two decades, OSA has emerged as a cardiometabolic risk factor in both paediatric and adult populations. OSA-induced metabolic perturbations include dyslipidaemia, atherogenesis, liver dysfunction and abnormal glucose metabolism. The mainstay of treatment for OSA is adenotonsillectomy in children and continuous positive airway pressure therapy in adults. Although these therapies are effective at resolving the sleep-disordered breathing component of OSA, they do not always produce beneficial effects on metabolic function. Thus, a deeper understanding of the underlying mechanisms by which OSA influences metabolic dysfunction might yield improved therapeutic approaches and outcomes. In this Review, we summarize the evidence obtained from animal models and studies of patients with OSA of potential mechanistic pathways linking the hallmarks of OSA (intermittent hypoxia and sleep fragmentation) with metabolic dysfunction. Special emphasis is given to adipose tissue dysfunction induced by sleep apnoea, which bears a striking resemblance to adipose dysfunction resulting from obesity. In addition, important gaps in current knowledge and promising lines of future investigation are identified.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanisms of adipose tissue dysfunction resulting from chronic intermittent hypoxia and sleep fragmentation based on animal models.

Similar content being viewed by others

References

  1. Peppard, P. E. et al. Increased prevalence of sleep-disordered breathing in adults. Am. J. Epidemiol. 177, 1006–1014 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Redline, S. et al. Sleep-disordered breathing in Hispanic/Latino individuals of diverse backgrounds. The Hispanic Community Health Study/Study of Latinos. Am. J. Respir. Crit. Care Med. 189, 335–344 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sanchez-de-la-Torre, M., Campos-Rodriguez, F. & Barbe, F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir. Med. 1, 61–72 (2013).

    Article  PubMed  Google Scholar 

  4. Goncalves, M. et al. Sleepiness at the wheel across Europe: a survey of 19 countries. J. Sleep Res. 24, 242–253 (2015).

    Article  PubMed  Google Scholar 

  5. Lacasse, Y., Godbout, C. & Series, F. Health-related quality of life in obstructive sleep apnoea. Eur. Respir. J. 19, 499–503 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Young, T. et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 31, 1071–1078 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Martinez-Ceron, E., Fernandez-Navarro, I. & Garcia-Rio, F. Effects of continuous positive airway pressure treatment on glucose metabolism in patients with obstructive sleep apnea. Sleep Med. Rev. 25, 121–130 (2015).

    Article  PubMed  Google Scholar 

  8. Hakim, F., Kheirandish-Gozal, L. & Gozal, D. Obesity and altered sleep: a pathway to metabolic derangements in children? Semin. Pediatr. Neurol. 22, 77–85 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Koren, D., O'Sullivan, K. L. & Mokhlesi, B. Metabolic and glycemic sequelae of sleep disturbances in children and adults. Curr. Diab. Rep. 15, 562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tanno, S. et al. Sleep-related intermittent hypoxemia and glucose intolerance: a community-based study. Sleep Med. 15, 1212–1218 (2014).

    Article  PubMed  Google Scholar 

  11. Hendricks, J. C. et al. The English bulldog: a natural model of sleep-disordered breathing. J. Appl. Physiol. (1985) 63, 1344–1350 (1987).

    Article  Google Scholar 

  12. Brennick, M. J. et al. Tongue fat infiltration in obese versus lean Zucker rats. Sleep 37, 1095–1102 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chopra, S., Polotsky, V. Y. & Jun, J. C. Sleep apnea research in animals: past, present, and future. Am. J. Respir. Cell. Mol. Biol. http://dx.doi.org/10.1165/rcmb.2015-0218TR, (2015).

  14. Carreras, A., Wang, Y. & Gozal, D. in Encyclopedia of Sleep (ed. Kushida, C.) 184–191 (Academic Press, 2013).

    Book  Google Scholar 

  15. Almendros, I., Wang, Y. & Gozal, D. The polymorphic and contradictory aspects of intermittent hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L129–L140 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tagaito, Y. et al. A model of sleep-disordered breathing in the C57BL/6J mouse. J. Appl. Physiol. (1985) 91, 2758–2766 (2001).

    Article  Google Scholar 

  17. Unnikrishnan, D., Jun, J. & Polotsky, V. Inflammation in sleep apnea: an update. Rev. Endocr. Metab. Disord. 16, 25–34 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schulz, R. et al. Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2. J. Hypertens. 32, 300–305 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Drager, L. F. et al. Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4. Am. J. Respir. Crit. Care Med. 188, 240–248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Iiyori, N. et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am. J. Respir. Crit. Care Med. 175, 851–857 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Drager, L. F., Jun, J. C. & Polotsky, V. Y. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract. Res. Clin. Endocrinol. Metab. 24, 843–851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Louis, M. & Punjabi, N. M. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J. Appl. Physiol. (1985) 106, 1538–1544 (2009).

    Article  CAS  Google Scholar 

  23. Tamisier, R. et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur. Respir. J. 37, 119–128 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Stamatakis, K. A. & Punjabi, N. M. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 137, 95–101 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Trzepizur, W. et al. Independent association between nocturnal intermittent hypoxemia and metabolic dyslipidemia. Chest 143, 1584–1589 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Newman, A. B. et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am. J. Epidemiol. 154, 50–59 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Wu, W. T. et al. The association between obstructive sleep apnea and metabolic markers and lipid profiles. PLoS ONE 10, e0130279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jun, J. C. et al. Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure. Sleep 34, 1207–1213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Barcelo, A. et al. Free fatty acids and the metabolic syndrome in patients with obstructive sleep apnoea. Eur. Respir. J. 37, 1418–1423 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Robinson, G. V., Pepperell, J. C., Segal, H. C., Davies, R. J. & Stradling, J. R. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 59, 777–782 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chirinos, J. A. et al. CPAP, weight loss, or both for obstructive sleep apnea. N. Engl. J. Med. 370, 2265–2275 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rebelo, S., Drummond, M. & Marques, J. A. Lipid profile after long-term APAP in OSA patients. Sleep Breath. 19, 931–937 (2015).

    Article  PubMed  Google Scholar 

  33. Phillips, C. L. et al. Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial. Am. J. Respir. Crit. Care Med. 184, 355–361 (2011).

    Article  PubMed  Google Scholar 

  34. Sivam, S. et al. Effects of 8 weeks of CPAP on lipid-based oxidative markers in obstructive sleep apnea: a randomized trial. J. Sleep Res. 24, 339–345 (2015).

    Article  PubMed  Google Scholar 

  35. Nadeem, R. et al. Effect of CPAP treatment for obstructive sleep apnea hypopnea syndrome on lipid profile: a meta-regression analysis. J. Clin. Sleep Med. 10, 1295–1302 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Jullian-Desayes, I. et al. Impact of obstructive sleep apnea treatment by continuous positive airway pressure on cardiometabolic biomarkers: a systematic review from sham CPAP randomized controlled trials. Sleep Med. Rev. 21, 23–38 (2015).

    Article  PubMed  Google Scholar 

  37. Tauman, R., O'Brien, L. M., Ivanenko, A. & Gozal, D. Obesity rather than severity of sleep-disordered breathing as the major determinant of insulin resistance and altered lipidemia in snoring children. Pediatrics 116, E66–E73 (2005).

    Article  PubMed  Google Scholar 

  38. Koren, D., Gozal, D., Bhattacharjee, R., Philby, M. & Kheirandish-Gozal, L. Impact of adenotonsillectomy on insulin resistance and lipoprotein profile in nonobese and obese children. Chest http://dx.doi.org/10.1378/chest.15-1543, (2015).

  39. Van Hoorenbeeck, K. et al. Metabolic disregulation in obese adolescents with sleep-disordered breathing before and after weight loss. Obesity (Silver Spring) 21, 1446–1450 (2013).

    Article  CAS  Google Scholar 

  40. Quante, M. et al. The effect of adenotonsillectomy for childhood sleep apnea on cardiometabolic measures. Sleep 38, 1395–1403 (2014).

    Google Scholar 

  41. Ip, M. S. et al. Obstructive sleep apnea is independently associated with insulin resistance. Am. J. Respir. Crit. Care Med. 165, 670–676 (2002).

    Article  PubMed  Google Scholar 

  42. Pamidi, S. et al. Obstructive sleep apnea in young lean men: impact on insulin sensitivity and secretion. Diabetes Care 35, 2384–2389 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Punjabi, N. M. et al. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am. J. Epidemiol. 160, 521–530 (2004).

    Article  PubMed  Google Scholar 

  44. Parish, J. M., Adam, T. & Facchiano, L. Relationship of metabolic syndrome and obstructive sleep apnea. J. Clin. Sleep Med. 3, 467–472 (2007).

    PubMed  PubMed Central  Google Scholar 

  45. Muraki, I. et al. Nocturnal intermittent hypoxia and the development of type 2 diabetes: the Circulatory Risk in Communities Study (CIRCS). Diabetologia 53, 481–488 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Tasali, E., Mokhlesi, B. & Van Cauter, E. Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest 133, 496–506 (2008).

    Article  PubMed  Google Scholar 

  47. Babu, A. R., Herdegen, J., Fogelfeld, L., Shott, S. & Mazzone, T. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch. Intern. Med. 165, 447–452 (2005).

    Article  PubMed  Google Scholar 

  48. Grimaldi, D., Beccuti, G., Touma, C., Van Cauter, E. & Mokhlesi, B. Association of obstructive sleep apnea in rapid eye movement sleep with reduced glycemic control in type 2 diabetes: therapeutic implications. Diabetes Care 37, 355–363 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Aronsohn, R. S., Whitmore, H., Van Cauter, E. & Tasali, E. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am. J. Respir. Crit. Care Med. 181, 507–513 (2010).

    Article  PubMed  Google Scholar 

  50. Foster, G. D. et al. Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 32, 1017–1019 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mokhlesi, B., Ham, S. A. & Gozal, D. The effect of sex and age on the comorbidity burden of OSA: an observational analysis from a large nationwide US health claims database. Eur. Respir. J. http://dx.doi.org/10.1183/13993003.01618-2015 (2016).

  52. Harsch, I. A. et al. The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes. Respiration 71, 252–259 (2004).

    Article  PubMed  Google Scholar 

  53. Harsch, I. A. et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am. J. Respir. Crit. Care Med. 169, 156–162 (2004).

    Article  PubMed  Google Scholar 

  54. Guest, J. F., Panca, M., Sladkevicius, E., Taheri, S. & Stradling, J. Clinical outcomes and cost-effectiveness of continuous positive airway pressure to manage obstructive sleep apnea in patients with type 2 diabetes in the UK. Diabetes Care 37, 1263–1271 (2014).

    Article  PubMed  Google Scholar 

  55. West, S. D., Nicoll, D. J., Wallace, T. M., Matthews, D. R. & Stradling, J. R. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 62, 969–974 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hoyos, C. M. et al. Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study. Thorax 67, 1081–1089 (2012).

    Article  PubMed  Google Scholar 

  57. Lam, J. C., Tan, K. C., Lai, A. Y., Lam, D. C. & Ip, M. S. Increased serum levels of advanced glycation end-products is associated with severity of sleep disordered breathing but not insulin sensitivity in non-diabetic men with obstructive sleep apnoea. Sleep Med. 13, 15–20 (2012).

    Article  PubMed  Google Scholar 

  58. Weinstock, T. G. et al. A controlled trial of CPAP therapy on metabolic control in individuals with impaired glucose tolerance and sleep apnea. Sleep 35, 617–625B (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Iftikhar, I. H., Hoyos, C. M., Phillips, C. L. & Magalang, U. J. Meta-analyses of the association of sleep apnea with insulin resistance, and the effects of CPAP on HOMA-IR, adiponectin, and visceral adipose fat. J. Clin. Sleep Med. 11, 475–485 (2015).

    PubMed  PubMed Central  Google Scholar 

  60. Schahin, S. P. et al. Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome. Med. Sci. Monit. 14, CR117–CR121 (2008).

    CAS  PubMed  Google Scholar 

  61. Pamidi, S. et al. Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial. Am. J. Respir. Crit. Care Med. 192, 96–105 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gozal, D., Capdevila, O. S. & Kheirandish-Gozal, L. Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children. Am. J. Respir. Crit. Care Med. 177, 1142–1149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shamsuzzaman, A., Szczesniak, R. D., Fenchel, M. C. & Amin, R. S. Glucose, insulin, and insulin resistance in normal-weight, overweight and obese children with obstructive sleep apnea. Obes Res. Clin. Pract. 8, e584–e591 (2014).

    Article  PubMed  Google Scholar 

  64. Lesser, D. J. et al. Sleep fragmentation and intermittent hypoxemia are associated with decreased insulin sensitivity in obese adolescent Latino males. Pediatr. Res. 72, 293–298 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li, J. et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J. Appl. Physiol. (1985) 99, 1643–1648 (2005).

    Article  CAS  Google Scholar 

  66. Li, J. G. et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circul. Res. 97, 698–706 (2005).

    Article  CAS  Google Scholar 

  67. Li, J. et al. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J. Appl. Physiol. (1985) 102, 557–563 (2007).

    Article  CAS  Google Scholar 

  68. Drager, L. F. et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur. Heart J. 33, 783–790 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Drager, L. F. et al. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 19, 2167–2174 (2011).

    Article  CAS  Google Scholar 

  70. Van Noolen, L. et al. Docosahexaenoic acid supplementation modifies fatty acid incorporation in tissues and prevents hypoxia induced-atherosclerosis progression in apolipoprotein-E deficient mice. Prostaglandins Leukot. Essent. Fatty Acids 91, 111–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Ferrarini, A. et al. Fingerprinting-based metabolomic approach with LC-MS to sleep apnea and hypopnea syndrome: a pilot study. Electrophoresis 34, 2873–2881 (2013).

    CAS  PubMed  Google Scholar 

  72. Carreras, A. et al. Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice. Endocrinology 156, 437–443 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Nachalon, Y., Lowenthal, N., Greenberg-Dotan, S. & Goldbart, A. D. Inflammation and growth in young children with obstructive sleep apnea syndrome before and after adenotonsillectomy. Mediators Inflamm. 2014, 146893 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ogretmenoglu, O., Suslu, A. E., Yucel, O. T., Onerci, T. M. & Sahin, A. Body fat composition: a predictive factor for obstructive sleep apnea. Laryngoscope 115, 1493–1498 (2005).

    Article  PubMed  Google Scholar 

  75. Garcia-Fuentes, E. et al. Hypoxia is associated with a lower expression of genes involved in lipogenesis in visceral adipose tissue. J. Transl. Med. 13, 373 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hodson, L. Adipose tissue oxygenation: effects on metabolic function. Adipocyte 3, 75–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Kayser, B. & Verges, S. Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies. Obes. Rev. 14, 579–592 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Pasarica, M. et al. Reduced oxygenation in human obese adipose tissue is associated with impaired insulin suppression of lipolysis. J. Clin. Endocrinol. Metab. 95, 4052–4055 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Trayhurn, P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu. Rev. Nutr. 34, 207–236 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Pasarica, M. et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58, 718–725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fujisaka, S. et al. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice. Diabetologia 56, 1403–1412 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Kim, D. H., Gutierrez-Aguilar, R., Kim, H. J., Woods, S. C. & Seeley, R. J. Increased adipose tissue hypoxia and capacity for angiogenesis and inflammation in young diet-sensitive C57 mice compared with diet-resistant FVB mice. Int. J. Obes. (Lond.) 37, 853–860 (2013).

    Article  CAS  Google Scholar 

  83. Hodson, L., Humphreys, S. M., Karpe, F. & Frayn, K. N. Metabolic signatures of human adipose tissue hypoxia in obesity. Diabetes 62, 1417–1425 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Matsuura, H. et al. Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance. Circulation 127, 2078–2087 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Rahtu-Korpela, L. et al. HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. Diabetes 63, 3324–3333 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Choe, S. S. et al. Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity. Diabetes 63, 3359–3371 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Jiang, C. et al. Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes 60, 2484–2495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lee, Y. S. et al. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell 157, 1339–1352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Scalia, R. The microcirculation in adipose tissue inflammation. Rev. Endocr. Metab. Disord. 14, 69–76 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shimizu, I. et al. Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. 124, 2099–2112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Villela, N. R., Kramer-Aguiar, L. G., Bottino, D. A., Wiernsperger, N. & Bouskela, E. Metabolic disturbances linked to obesity: the role of impaired tissue perfusion. Arq. Bras. Endocrinol. Metabol. 53, 238–245 (2009).

    Article  PubMed  Google Scholar 

  92. Michailidou, Z. et al. Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11β-hydroxysteroid dehydrogenase type 1 (HSD1)-deficient mice. J. Biol. Chem. 287, 4188–4197 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Farb, M. G. et al. Arteriolar function in visceral adipose tissue is impaired in human obesity. Arterioscler. Thromb. Vasc. Biol. 32, 467–473 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Hill, A. A., Reid Bolus, W. & Hasty, A. H. A decade of progress in adipose tissue macrophage biology. Immunol. Rev. 262, 134–152 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Martinez-Santibanez, G. & Lumeng, C. N. Macrophages and the regulation of adipose tissue remodeling. Annu. Rev. Nutr. 34, 57–76 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Schipper, H. S., Prakken, B., Kalkhoven, E. & Boes, M. Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol. Metab. 23, 407–415 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Mathis, D. Immunological goings-on in visceral adipose tissue. Cell Metab. 17, 851–859 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ghigliotti, G. et al. Adipose tissue immune response: novel triggers and consequences for chronic inflammatory conditions. Inflammation 37, 1337–1353 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. O'Rourke, R. W. et al. Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring) 22, 2109–2114 (2014).

    Article  CAS  Google Scholar 

  100. Morris, D. L. et al. Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62, 2762–2772 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cipolletta, D. Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 142, 517–525 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee, J. H., Gao, Z. & Ye, J. Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α. Am. J. Physiol. Endocrinol. Metab. 304, E1035–1041 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cho, K. W. et al. An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep. 9, 605–617 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Poulain, L. et al. Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis. Eur. Respir. J. 43, 513–522 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Poulain, L., Richard, V., Levy, P., Dematteis, M. & Arnaud, C. Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia. Mediators Inflamm. 2015, 620258 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Carreras, A. et al. Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R700–R709 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lee, E. J. et al. Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia. Eur. J. Appl. Physiol. 113, 467–478 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Olea, E. et al. Intermittent hypoxia and diet-induced obesity: effects on oxidative status, sympathetic tone, plasma glucose and insulin levels, and arterial pressure. J. Appl. Physiol. (1985) 117, 706–719 (2014).

    Article  CAS  Google Scholar 

  109. van den Borst, B. et al. Characterization of the inflammatory and metabolic profile of adipose tissue in a mouse model of chronic hypoxia. J. Appl. Physiol. (1985) 114, 1619–1628 (2013).

    Article  CAS  Google Scholar 

  110. Jun, J. C. et al. Thermoneutrality modifies the impact of hypoxia on lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 304, E424–E435 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Jun, J. C. et al. Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice. Am. J. Physiol. Endocrinol. Metab. 303, E377–E388 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mesarwi, O. A., Sharma, E. V., Jun, J. C. & Polotsky, V. Y. Metabolic dysfunction in obstructive sleep apnea: a critical examination of underlying mechanisms. Sleep Biol. Rhythms 13, 2–17 (2015).

    Article  PubMed  Google Scholar 

  113. Gharib, S. A. et al. Intermittent hypoxia activates temporally coordinated transcriptional programs in visceral adipose tissue. J. Mol. Med. (Berl.) 90, 435–445 (2012).

    Article  CAS  Google Scholar 

  114. He, Q. et al. Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. PLoS ONE 9, e86326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fiori, C. Z. et al. Downregulation of uncoupling protein-1 mRNA expression and hypoadiponectinemia in a mouse model of sleep apnea. Sleep Breath. 18, 541–548 (2014).

    Article  PubMed  Google Scholar 

  116. Reinke, C., Bevans-Fonti, S., Drager, L. F., Shin, M. K. & Polotsky, V. Y. Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes. J. Appl. Physiol. (1985) 111, 881–890 (2011).

    Article  Google Scholar 

  117. Zuo, L., Pannell, B. K., Re, A. T., Best, T. M. & Wagner, P. D. Po2 cycling protects diaphragm function during reoxygenation via ROS, Akt, ERK, and mitochondrial channels. Am. J. Physiol. Cell Physiol. 309, C759–C766 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Nair, D., Dayyat, E. A., Zhang, S. X., Wang, Y. & Gozal, D. Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS ONE 6, e19847 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kumar, G. K., Peng, Y. J., Nanduri, J. & Prabhakar, N. R. Carotid body chemoreflex mediates intermittent hypoxia-induced oxidative stress in the adrenal medulla. Adv. Exp. Med. Biol. 860, 195–199 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lin, M. et al. Structural remodeling of nucleus ambiguus projections to cardiac ganglia following chronic intermittent hypoxia in C57BL/6J mice. J. Comp. Neurol. 509, 103–117 (2008).

    Article  PubMed  Google Scholar 

  121. Gu, H. et al. Selective impairment of central mediation of baroreflex in anesthetized young adult Fischer 344 rats after chronic intermittent hypoxia. Am. J. Physiol. Heart Circ. Physiol. 293, H2809–H2818 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Chalacheva, P., Thum, J., Yokoe, T., O'Donnell, C. P. & Khoo, M. C. Development of autonomic dysfunction with intermittent hypoxia in a lean murine model. Respir. Physiol. Neurobiol. 188, 143–151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Delarue, J. & Magnan, C. Free fatty acids and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 10, 142–148 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Semenza, G. L. & Prabhakar, N. R. Neural regulation of hypoxia-inducible factors and redox state drives the pathogenesis of hypertension in a rodent model of sleep apnea. 119, 1152–1156 (2015).

  126. Saito, Y. et al. Loss of SDHB elevates catecholamine synthesis and secretion depending on ROS production & HIF Stabilization. Neurochem. Res. http://dx.doi.org/10.1007/s11064-015-1738-3 (2015).

  127. Jacintho, J. D. & Kovacic, P. Neurotransmission and neurotoxicity by nitric oxide, catecholamines, and glutamate: unifying themes of reactive oxygen species and electron transfer. Curr. Med. Chem. 10, 2693–2703 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Jun, J. C. et al. Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy. Am. J. Physiol. Endocrinol. Metab. 307, E1073–E1083 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shin, M. K. et al. Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia. J. Appl. Physiol. (1985) 117, 765–776 (2014).

    Article  CAS  Google Scholar 

  130. Haneklaus, M. & O'Neill, L. A. NLRP3 at the interface of metabolism and inflammation. Immunol. Rev. 265, 53–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Wang, Q. et al. Resveratrol attenuates intermittent hypoxia-induced insulin resistance in rats: involvement of Sirtuin 1 and the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway. Mol. Med. Rep. 11, 151–158 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Corey, K. E. et al. Obstructive sleep apnea is associated with nonalcoholic steatohepatitis and advanced liver histology. Dig. Dis. Sci. 60, 2523–2528 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Kheirandish-Gozal, L., Sans Capdevila, O., Kheirandish, E. & Gozal, D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest 133, 92–99 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Savransky, V. et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G871–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Savransky, V. et al. Chronic intermittent hypoxia predisposes to liver injury. Hepatology 45, 1007–1013 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Polak, J. et al. Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep 36, 1483–1490 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. da Rosa, D. P. et al. Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea. Inflamm. Res. 64, 21–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. da Rosa, D. P. et al. Simulating sleep apnea by exposure to intermittent hypoxia induces inflammation in the lung and liver. Mediators Inflamm. 2012, 879419 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Li, J. et al. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1α. Physiol. Genomics 25, 450–457 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Mirrakhimov, A. E. & Polotsky, V. Y. Obstructive sleep apnea and non-alcoholic fatty liver disease: is the liver another target? Front. Neurol. 3, 149 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sherwani, S. I. et al. Intermittent hypoxia exacerbates pancreatic β-cell dysfunction in a mouse model of diabetes mellitus. Sleep 36, 1849–1858 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Wang, N., Khan, S. A., Prabhakar, N. R. & Nanduri, J. Impaired pancreatic β-cell function by chronic intermittent hypoxia. Exp. Physiol. 98, 1376–1385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Pae, E. K. & Kim, G. Insulin production hampered by intermittent hypoxia via impaired zinc homeostasis. PLoS ONE 9, e90192 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ota, H. et al. Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. Life Sci. 93, 664–672 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Ota, H. et al. Attenuation of glucose-induced insulin secretion by intermittent hypoxia via down-regulation of CD38. Life Sci. 90, 206–211 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Xu, J., Long, Y. S., Gozal, D. & Epstein, P. N. β-cell death and proliferation after intermittent hypoxia: role of oxidative stress. Free Radic. Biol. Med. 46, 783–790 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Yokoe, T. et al. Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta-cell replication in mice. J. Physiol. 586, 899–911 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Lo, J. F. et al. Islet preconditioning via multimodal microfluidic modulation of intermittent hypoxia. Anal. Chem. 84, 1987–1993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fang, Y. et al. Intermittent hypoxia-induced rat pancreatic β-cell apoptosis and protective effects of antioxidant intervention. Nutr. Diabetes 4, e131 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Shin, M. K. et al. The effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia. Respir. Physiol. Neurobiol. 203, 60–67 (2014).

    Article  PubMed  Google Scholar 

  153. Greenhill, C. Gut microbiota: Firmicutes and Bacteroidetes involved in insulin resistance by mediating levels of glucagon-like peptide 1. Nat. Rev. Endocrinol. 11, 254 (2015).

    Article  PubMed  Google Scholar 

  154. Hartstra, A. V., Bouter, K. E., Backhed, F. & Nieuwdorp, M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 38, 159–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Parekh, P. J., Arusi, E., Vinik, A. I. & Johnson, D. A. The role and influence of gut microbiota in pathogenesis and management of obesity and metabolic syndrome. Front. Endocrinol. (Lausanne) 5, 47 (2014).

    Article  Google Scholar 

  156. Khan, M. T., Nieuwdorp, M. & Backhed, F. Microbial modulation of insulin sensitivity. Cell Metab. 20, 753–760 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Kheirandish-Gozal, L. et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J. Clin. Endocrinol. Metab. 99, 656–663 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Nobili, V. et al. Altered gut-liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver. Thorax 70, 769–781 (2015).

    Article  PubMed  Google Scholar 

  161. Moreno-Indias, I. et al. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur. Respir. J. 45, 1055–1065 (2015).

    Article  PubMed  Google Scholar 

  162. Jouvet, D., Vimont, P., Delorme, F. & Jouvet, M. Etude de la privation sélective de la phase paradoxale de sommeil chez le chat. C.R. Soc. Biol. 23, 756–759 (1964).

    Google Scholar 

  163. Tartar, J. L. et al. Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation. Eur. J. Neurosci. 23, 2739–2748 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Kaushal, N., Ramesh, V. & Gozal, D. TNF-α and temporal changes in sleep architecture in mice exposed to sleep fragmentation. PLoS ONE 7, e45610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ramesh, V. et al. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway. J. Neuroinflamm. 9, 91 (2012).

    CAS  Google Scholar 

  166. Kaushal, N., Ramesh, V. & Gozal, D. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R19–R29 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kaushal, N., Nair, D., Gozal, D. & Ramesh, V. Socially isolated mice exhibit a blunted homeostatic sleep response to acute sleep deprivation compared to socially paired mice. Brain Res. 1454, 65–79 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Nair, D. et al. Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am. J. Respir. Crit. Care Med. 184, 1305–1312 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Leenaars, C. H. et al. Switch-task performance in rats is disturbed by 12 h of sleep deprivation but not by 12 h of sleep fragmentation. Sleep 35, 211–221 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Tartar, J. L. et al. Sleep fragmentation reduces hippocampal CA1 pyramidal cell excitability and response to adenosine. Neurosci. Lett. 469, 1–5 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Wang, Y. et al. Chronic sleep fragmentation promotes obesity in young adult mice. Obesity (Silver Spring) 22, 758–762 (2014).

    Article  CAS  Google Scholar 

  172. Zhang, S. X. et al. Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice. Int. J. Obes. (Lond.) 38, 619–624 (2014).

    Article  CAS  Google Scholar 

  173. Nair, D. et al. Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase–dependent pathways in mouse. Am. J. Respir. Crit. Care Med. 184, 1305–1312 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Carreras, A. et al. Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice. Sleep 37, 1817–1824 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Smith, S. S., Waight, C., Doyle, G., Rossa, K. R. & Sullivan, K. A. Liking for high fat foods in patients with obstructive sleep apnoea. Appetite 78, 185–192 (2014).

    Article  PubMed  Google Scholar 

  176. Spruyt, K., Sans Capdevila, O., Serpero, L. D., Kheirandish-Gozal, L. & Gozal, D. Dietary and physical activity patterns in children with obstructive sleep apnea. J. Pediatr. 156, 724–730.e3 (2010).

    Article  PubMed  Google Scholar 

  177. Beebe, D. W., Miller, N., Kirk, S., Daniels, S. R. & Amin, R. The association between obstructive sleep apnea and dietary choices among obese individuals during middle to late childhood. Sleep Med. 12, 797–799 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Chihara, Y. et al. Among metabolic factors, significance of fasting and postprandial increases in acyl and desacyl ghrelin and the acyl/desacyl ratio in obstructive sleep apnea before and after treatment. J. Clin. Sleep Med. 11, 895–905 (2015).

    PubMed  PubMed Central  Google Scholar 

  179. Ong, C. W., O'Driscoll, D. M., Truby, H., Naughton, M. T. & Hamilton, G. S. The reciprocal interaction between obesity and obstructive sleep apnoea. Sleep Med. Rev. 17, 123–131 (2013).

    Article  PubMed  Google Scholar 

  180. Hakim, F. et al. Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice. Sleep 38, 31–40 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Gharib, S. A., Khalyfa, A., Abdelkarim, A., Bhushan, B. & Gozal, D. Integrative miRNA-mRNA profiling of adipose tissue unravels transcriptional circuits induced by sleep fragmentation. PLoS ONE 7, e37669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Khalyfa, A. et al. Sleep fragmentation in mice induces nicotinamide adenine dinucleotide phosphate oxidase 2-dependent mobilization, proliferation, and differentiation of adipocyte progenitors in visceral white adipose tissue. Sleep 37, 999–1009 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Carreras, A. et al. Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea. Int. J. Obes. (Lond.) 39, 418–423 (2015).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Biological Sciences Division, Section of Sleep Medicine, Pritzker School of Medicine, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637–1470, USA,

    Alex Gileles-Hillel, Leila Kheirandish-Gozal & David Gozal

Authors
  1. Alex Gileles-Hillel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leila Kheirandish-Gozal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Gozal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.G-H, L.K-G and D.G. researched data for the article, contributed to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission

Corresponding author

Correspondence to David Gozal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gileles-Hillel, A., Kheirandish-Gozal, L. & Gozal, D. Biological plausibility linking sleep apnoea and metabolic dysfunction. Nat Rev Endocrinol 12, 290–298 (2016). https://doi.org/10.1038/nrendo.2016.22

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.22

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing