Exp Clin Endocrinol Diabetes 2009; 117(3): 129-134
DOI: 10.1055/s-2008-1078738
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Intermittent Hypoxia Suppresses Adiponectin Secretion by Adipocytes

U. J. Magalang 1 , 3 , J. P. Cruff 1 , 3 , R. Rajappan 1 , 3 , M. G. Hunter 1 , 3 , T. Patel 1 , 3 , C. B. Marsh 1 , 3 , S. V. Raman 2 , 3 , N. L. Parinandi 1 , 3
  • 1Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio, USA
  • 2Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA
  • 3Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA
Further Information

Publication History

received 04.01.2008 first decision 25.03.2008

accepted 15.05.2008

Publication Date:
19 June 2008 (online)

Abstract

Obstructive sleep apnea (OSA), characterized by cyclic intermittent hypoxia (IH) during sleep, is an independent risk factor for cardiovascular disease. Adiponectin (APN), an adipocytokine secreted exclusively by adipocytes, possesses antiatherogenic properties. Low levels of APN, particularly the high-molecular-weight (HMW) form, are associated with an increased risk of cardiovascular disease. Here, we hypothesized that IH would result in the dysregulation of APN expression and secretion. 3T3-L1 adipocytes were exposed to IH at 12 cycles/h for 6 h/d to simulate the IH condition similar to that encountered in OSA. Control adipocytes were exposed to 21% O2 under identical conditions. After 48 h of incubation, IH caused a decrease in the secretion of total and HMW APN in spite of a significant upregulation of APN mRNA expression by adipocytes. This study suggested a novel mechanism of how the cyclic hypoxemia in OSA predisposes OSA patients to cardiovascular disease through the dysregulation of secretion of APN by adipocytes. Further studies are needed to determine the exact molecular mechanism how IH reduces the release of APN by adipocytes.

References

  • 1 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K. et al . Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 ((1)) 79-83
  • 2 Aso Y, Yamamoto R, Wakabayashi S, Uchida T, Takayanagi K. et al . Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosor-bent assay to detect HMW adiponectin.  Diabetes. 2006;  55 ((7)) 1954-1960
  • 3 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease.  Circ Res. 2005;  96 ((9)) 939-949
  • 4 Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism.  Trends Endocrinol Metab. 2002;  13 ((2)) 84-89
  • 5 Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model.  J Clin Invest. 1997;  99 ((1)) 106-109
  • 6 Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone?.  Diabetes Care. 2003;  26 ((8)) 2442-2450
  • 7 Chen B, Lam KS, Wang Y, Wu D, Lam MC. et al . Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.  Biochem Biophys Res Commun. 2006;  341 ((2)) 549-556
  • 8 Goldstein BJ, Scalia R. Adiponectin: A novel adipokine linking adipocytes and vascular function.  J Clin Endocrinol Metab. 2004;  89 ((6)) 2563-2568
  • 9 Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O. et al . Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome.  Diabetes Care. 2006;  29 ((6)) 1357-1362
  • 10 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S. et al . Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.  Diabetes. 2007;  56 ((4)) 901-911
  • 11 Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M. et al . Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.  Circ Res. 2004;  94 ((4)) e27-31
  • 12 Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology.  Am J Physiol Regul Integr Comp Physiol. 2004;  287 ((5)) R1014-1030
  • 13 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.  Methods. 2001;  25 ((4)) 402-408
  • 14 Magalang UJ, Rajappan R, Hunter MG, Kutala VK, Kuppusamy P. et al . Adiponectin inhibits superoxide generation by human neutrophils.  Antioxid Redox Signal. 2006;  8 ((11–12)) 2179-2186
  • 15 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.  Lancet. 2005;  365 ((9464)) 1046-1053
  • 16 Minoguchi K, Tazaki T, Yokoe T, Minoguchi H, Watanabe Y. et al . Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome.  Chest. 2004;  126 ((5)) 1473-1479
  • 17 Motoshima H, Wu X, Mahadev K, Goldstein BJ. Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL.  Biochem Biophys Res Commun. 2004;  315 ((2)) 264-271
  • 18 Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y. et al . Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.  Circulation. 2002;  106 ((22)) 2767-2770
  • 19 Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T. et al . Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.  J Biol Chem. 2004;  279 ((13)) 12152-12162
  • 20 Sato C, Yasukawa Z, Honda N, Matsuda T, Kitajima K. Identification and adipocyte differentiation-dependent expression of the unique disialic acid residue in an adipose tissue-specific glycoprotein, adipo Q.  J Biol Chem. 2001;  276 ((31)) 28849-28856
  • 21 Savransky V, Nanayakkara A, Li J, Bevans S, Smith PL. et al . Chronic intermittent hypoxia induces atherosclerosis.  Am J Respir Crit Care Med. 2007;  175 ((12)) 1290-1297
  • 22 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 ((45)) 26746-26749
  • 23 Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H. et al . Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy.  Am J Respir Crit Care Med. 2000;  162 ((2 Pt 1)) 566-570
  • 24 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue.  Br J Nutr. 2004;  92 ((3)) 347-355
  • 25 Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S. et al . Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.  J Biol Chem. 2003;  278 ((41)) 40352-40363
  • 26 Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes.  Pflugers Arch. 2007; 
  • 27 Wang Y, Lam KS, Yau MH, Xu A. Post-translational modifications of adiponectin: mechanisms and functional implications.  Biochem J. 2008;  409 ((3)) 623-633
  • 28 Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin – a key adipokine in the metabolic syndrome.  Diabetes Obes Metab. 2006;  8 ((3)) 264-280
  • 29 Xie L, Boyle D, Sanford D, Scherer PE, Pessin JE. et al . Intracellular trafficking and secretion of adiponectin is dependent on GGA-coated vesicles.  J Biol Chem. 2006;  281 ((11)) 7253-7259
  • 30 Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice.  Am J Physiol Endocrinol Metab. 2007; 
  • 31 Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H. et al . Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.  Circulation. 2003;  107 ((8)) 1129-1134
  • 32 Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective.  Am J Respir Crit Care Med. 2002;  165 ((9)) 1217-1239

Correspondence

U. J. MagalangMD 

Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine

Davis Heart and Lung Research Institute, Room 201

The Ohio State University Medical Center

473 West 12th Avenue

Columbus

43210 OH

Phone: +614/247 77 07

Fax: +614/293 47 99

Email: magalang.1@osu.edu

    >