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Horm Metab Res 2011; 43(6): 380-385
DOI: 10.1055/s-0031-1273767
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Hypoxia Induces Apelin Expression in Human Adipocytes

K. Geiger1 , 2 , A. Muendlein1 , 2 , N. Stark1 , 2 , C. H. Saely1 , 2 , 3 , M. Wabitsch4 , P. Fraunberger5 , H. Drexel1 , 2 , 3 , 6
  • 1Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
  • 2Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein
  • 3Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
  • 4Division of Pediatric Endocrinology and Diabetes, University of Ulm, Ulm, Germany
  • 5Medical Central Laboratories, Feldkirch, Austria
  • 6Drexel University College of Medicine, Philadelphia, USA
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Publication History

received 08.09.2010

accepted 23.02.2011

Publication Date:
29 March 2011 (online)

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Abstract

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O2, 94% N, and 5% CO2). In addition, hypoxic conditions were mimicked by using CoCl2. The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α.

Key words

adipokines - white adipocytes - oxygen-regulated gene expression

References

  • 1 Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ.  Proc Nutr Soc. 2001;  60 329-339
    Search in Google Scholar
  • 2 Hotamisligil GS. Inflammation and metabolic disorders.  Nature. 2006;  444 860-867
    Search in Google Scholar
  • 3 Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis.  Nature. 2006;  444 847-853
    Search in Google Scholar
  • 4 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome.  Mol Cell Endocrinol. 2010;  314 1-16
    Search in Google Scholar
  • 5 Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance.  Int J Obes (Lond). 2009;  33 54-66
    Search in Google Scholar
  • 6 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.  Diabetes. 2007;  56 901-911
    Search in Google Scholar
  • 7 Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration.  Int J Obes (Lond). 2008;  32 451-463
    Search in Google Scholar
  • 8 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;  293 E1118-E1128
    Search in Google Scholar
  • 9 Cummins EP, Taylor CT. Hypoxia-responsive transcription factors.  Pflugers Arch. 2005;  450 363-371
    Search in Google Scholar
  • 10 Rocha S. Gene regulation under low oxygen: holding your breath for transcription.  Trends Biochem Sci. 2007;  32 389-397
    Search in Google Scholar
  • 11 Semenza GL. Life with oxygen.  Science. 2007;  318 62-64
    Search in Google Scholar
  • 12 Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RL, Zhang J, Xu A. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.  Biochem Biophys Res Commun. 2006;  341 549-556
    Search in Google Scholar
  • 13 Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes.  Int J Obes Relat Metab Disord. 2003;  27 1187-1195
    Search in Google Scholar
  • 14 Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y, Tanaka M, Nakagawa Y, Kihara S, Funahashi T, Komuro R, Matsuda M, Shimomura I. Visfatin in adipocytes is upregulated by hypoxia through HIF1alpha-dependent mechanism.  Biochem Biophys Res Commun. 2006;  349 875-882
    Search in Google Scholar
  • 15 Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes.  Pflugers Arch. 2007;  455 479-492
    Search in Google Scholar
  • 16 Wang B, Wood IS, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes.  J Endocrinol. 2008;  198 127-134
    Search in Google Scholar
  • 17 Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor.  Biochem Biophys Res Commun. 1998;  251 471-476
    Search in Google Scholar
  • 18 De Falco M, De Luca L, Onori N, Cavallotti I, Artigiano F, Esposito V, De Luca B, Laforgia V, Groeger AM, De Luca A. Apelin expression in normal human tissues.  In Vivo. 2002;  16 333-336
    Search in Google Scholar
  • 19 Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M. Molecular properties of apelin: tissue distribution and receptor binding.  Biochim Biophys Acta. 2001;  1538 162-171
    Search in Google Scholar
  • 20 Carpene C, Dray C, Attane C, Valet P, Portillo MP, Churruca I, Milagro FI, Castan-Laurell I. Expanding role for the apelin/APJ system in physiopathology.  J Physiol Biochem. 2007;  63 359-373
    Search in Google Scholar
  • 21 Farkasfalvi K, Stagg MA, Coppen SR, Siedlecka U, Lee J, Soppa GK, Marczin N, Szokodi I, Yacoub MH, Terracciano CM. Direct effects of apelin on cardiomyocyte contractility and electrophysiology.  Biochem Biophys Res Commun. 2007;  357 889-895
    Search in Google Scholar
  • 22 Dai T, Ramirez-Correa G, Gao WD. Apelin increases contractility in failing cardiac muscle.  Eur J Pharmacol. 2006;  553 222-228
    Search in Google Scholar
  • 23 Sunter D, Hewson AK, Dickson SL. Intracerebroventricular injection of apelin-13 reduces food intake in the rat.  Neurosci Lett. 2003;  353 1-4
    Search in Google Scholar
  • 24 Cox CM, D’Agostino SL, Miller MK, Heimark RL, Krieg PA. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo.  Dev Biol. 2006;  296 177-189
    Search in Google Scholar
  • 25 Boucher J, Masri B, Daviaud D, Gesta S, Guigne C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpene C, Audigier Y, Saulnier-Blache JS, Valet P. Apelin, a newly identified adipokine up-regulated by insulin and obesity.  Endocrinology. 2005;  146 1764-1771
    Search in Google Scholar
  • 26 Heinonen MV, Purhonen AK, Miettinen P, Paakkonen M, Pirinen E, Alhava E, Akerman K, Herzig KH. Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding.  Regul Pept. 2005;  130 7-13
    Search in Google Scholar
  • 27 Han S, Wang G, Qi X, Lee HM, Englander EW, Greeley Jr GH. A possible role for hypoxia-induced apelin expression in enteric cell proliferation.  Am J Physiol Regul Integr Comp Physiol. 2008;  294 R1832-R1839
    Search in Google Scholar
  • 28 Glassford AJ, Yue P, Sheikh AY, Chun HJ, Zarafshar S, Chan DA, Reaven GM, Quertermous T, Tsao PS. HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes.  Am J Physiol Endocrinol Metab. 2007;  293 E1590-E1596
    Search in Google Scholar
  • 29 Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation.  Int J Obes Relat Metab Disord. 2001;  25 8-15
    Search in Google Scholar
  • 30 Sheikh AY, Chun HJ, Glassford AJ, Kundu RK, Kutschka I, Ardigo D, Hendry SL, Wagner RA, Chen MM, Ali ZA, Yue P, Huynh DT, Connolly AJ, Pelletier MP, Tsao PS, Robbins RC, Quertermous T. In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure.  Am J Physiol Heart Circ Physiol. 2008;  294 H88-H98
    Search in Google Scholar
  • 31 Eyries M, Siegfried G, Ciumas M, Montagne K, Agrapart M, Lebrin F, Soubrier F. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis.  Circ Res. 2008;  103 432-440
    Search in Google Scholar
  • 32 Wang G, Qi X, Wei W, Englander EW, Greeley Jr GH. Characterization of the 5′-regulatory regions of the rat and human apelin genes and regulation of breast apelin by USF.  FASEB J. 2006;  20 2639-2641
    Search in Google Scholar
  • 33 Kasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, Hinuma S, Baba A. Apelin is a novel angiogenic factor in retinal endothelial cells.  Biochem Biophys Res Commun. 2004;  325 395-400
    Search in Google Scholar
  • 34 Masri B, Morin N, Cornu M, Knibiehler B, Audigier Y. Apelin (65–77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells.  FASEB J. 2004;  18 1909-1911
    Search in Google Scholar
  • 35 Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR. Biological action of leptin as an angiogenic factor.  Science. 1998;  281 1683-1686
    Search in Google Scholar
  • 36 Thompson MP, Trayhurn P. Effect of salicylate on the expression of adipokines and glucose transporters in human adipocytes is modulated by hypoxia.  Horm Metab Res. 2009;  41 649-652
    Search in Google Scholar

Correspondence

H. DrexelMD, FESC 

Full Professor of Medicine

Vorarlberg Institute for Vascular

Investigation and Treatment

(VIVIT)

Carinagasse 47

6800 Feldkirch

Austria

Phone: +43/5522/303 2600

Fax: +43/5522/303 7533

Email: vivit@lkhf.at