Skip to main content Accessibility help
×
Home

Cellular hypoxia and adipose tissue dysfunction in obesity: Symposium on ‘Frontiers in adipose tissue biology’

  • I. Stuart Wood (a1), Fátima Pérez de Heredia (a1), Bohan Wang (a1) and Paul Trayhurn (a1)

Abstract

Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFα, IL-1β, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Cellular hypoxia and adipose tissue dysfunction in obesity
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Cellular hypoxia and adipose tissue dysfunction in obesity
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Cellular hypoxia and adipose tissue dysfunction in obesity
      Available formats
      ×

Copyright

Corresponding author

*Corresponding author: Dr I. Stuart Wood, fax +44 151 706 5802, email i.s.wood@liverpool.ac.uk

References

Hide All
1.Zhang, Y, Proenca, R, Maffei, M et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425432.
2.Trayhurn, P & Beattie, JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60, 329339.
3.Trayhurn, P & Wood, IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92, 347355.
4.Fantuzzi, G (2005) Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115, 911919.
5.Rosen, ED & Spiegelman, BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444, 847853.
6.McPherson, K, Marsh, T & Brown, M (2007) Foresight. Tackling Obesities: Future Choices – Modelling Future Trends in Obesity and the Impact on Health, 2nd ed. London: The Stationery Office.
7.Phillips, LK & Prins, JB (2008) The link between abdominal obesity and the metabolic syndrome. Curr Hypertens Rep 10, 156164.
8.Cancer Research UK (2009) Bodyweight and risk of cancer in the UK. http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/bodyweight/
9.Engstrom, G, Hedblad, B, Stavenow, L et al. (2003) Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 52, 20972101.
10.Festa, A, D'Agostino, R Jr, Williams, K et al. (2001) The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25, 14071415.
11.Yudkin, JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes 27, Suppl. 3, S25S28.
12.Yudkin, JS, Stehouwer, CD, Emeis, JJ et al. (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19, 972978.
13.Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 8791.
14.Fain, JN (2006) Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 74, 443477.
15.Arita, Y, Kihara, S, Ouchi, N et al. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257, 7983.
16.Ouchi, N, Kihara, S, Arita, Y et al. (1999) Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100, 24732476.
17.Hotta, K, Funahashi, T, Arita, Y et al. (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20, 15951599.
18.Weisberg, SP, McCann, D, Desai, M et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 17961808.
19.Xu, H, Barnes, GT, Yang, Q et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 18211830.
20.Bouloumie, A, Curat, CA, Sengenes, C et al. (2005) Role of macrophage tissue infiltration in metabolic diseases. Curr Opin Clin Nutr Metab Care 8, 347354.
21.Curat, CA, Miranville, A, Sengenes, C et al. (2004) From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53, 12851292.
22.Fleischmann, E, Kurz, A, Niedermayr, M et al. (2005) Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg 15, 813819.
23.Rupnick, MA, Panigrahy, D, Zhang, CY et al. (2002) Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 99, 1073010735.
24.Lolmede, K, Durand de Saint Front, V, Galitzky, J et al. (2003) Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord 27, 11871195.
25.Ambrosini, G, Nath, AK, Sierra-Honigmann, MR et al. (2002) Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 277, 3460134609.
26.Grosfeld, A, Andre, J, Hauguel-De Mouzon, S et al. (2002) Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J Biol Chem 277, 4295342957.
27.Grosfeld, A, Zilberfarb, V, Turban, S et al. (2002) Hypoxia increases leptin expression in human PAZ6 adipose cells. Diabetologia 45, 527530.
28.Kabon, B, Nagele, A, Reddy, D et al. (2004) Obesity decreases perioperative tissue oxygenation. Anesthesiology 100, 274280.
29.Karpe, F, Fielding, BA, Ilic, V et al. (2002) Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 51, 24672473.
30.Skurk, T, Alberti-Huber, C, Herder, C et al. (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92, 10231033.
31.Brahimi-Horn, MC & Pouyssegur, J (2007) Oxygen, a source of life and stress. FEBS Lett 581, 35823591.
32.Semenza, GL & Wang, GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12, 54475454.
33.Wang, GL & Semenza, GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90, 43044308.
34.Semenza, GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8, 588594.
35.Semenza, GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721732.
36.Patel, SA & Simon, MC (2008) Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ 15, 628634.
37.Bardos, JI & Ashcroft, M (2005) Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta 1755, 107120.
38.Leonard, MO, Howell, K, Madden, SF et al. (2008) Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung. Am J Respir Crit Care Med 178, 977983.
39.Taylor, CT (2008) Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 586, 40554059.
40.Hosogai, N, Fukuhara, A, Oshima, K et al. (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901911.
41.Ye, J, Gao, Z, Yin, J et al. (2007) 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 293, E1118E1128.
42.Pasarica, M, Sereda, OR, Redman, LM et al. (2009) Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58, 718725.
43.Wang, B, Wood, IS & Trayhurn, P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455, 479492.
44.Wood, IS, Wang, B, Lorente-Cebrian, S et al. (2007) Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes. Biochem Biophys Res Commun 361, 468473.
45.Chen, B, Lam, KS, Wang, Y et al. (2006) Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 341, 549556.
46.Wang, B, Wood, IS & Trayhurn, P (2008) PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochem Biophys Res Commun 368, 8893.
47.Tanji, K, Irie, Y, Uchida, Y et al. (2003) Expression of metallothionein-III induced by hypoxia attenuates hypoxia-induced cell death in vitro. Brain Res 976, 125129.
48.Semenza, GL (2007) Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J 405, 19.
49.Regazzetti, C, Peraldi, P, Gremeaux, T et al. (2009) Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58, 95–103.
50.Yin, J, Gao, Z, He, Q et al. (2009) Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab 296, E333E342.
51.Wood, IS, Hunter, L & Trayhurn, P (2003) Expression of Class III facilitative glucose transporter genes (GLUT-10 and GLUT-12) in mouse and human adipose tissues. Biochem Biophys Res Commun 308, 4349.
52.Wood, IS & Trayhurn, P (2003) Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 89, 39.
53.Douen, A, Ramlal, T, Rastogi, S et al. (1990) Exercise induces recruitment of the ‘insulin-responsive glucose transporter’. Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J Biol Chem 265, 1342713430.
54.Zierath, JR, Tsao, TS, Stenbit, AE et al. (1998) Restoration of hypoxia-stimulated glucose uptake in GLUT4-deficient muscles by muscle-specific GLUT4 transgenic complementation. J Biol Chem 273, 2091020915.
55.Meredith, D & Christian, HC (2008) The SLC16 monocaboxylate transporter family. Xenobiotica 38, 10721106.
56.Ullah, MS, Davies, AJ & Halestrap, AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281, 90309037.
57.de Luca, C & Olefsky, JM (2008) Inflammation and insulin resistance. FEBS Lett 582, 97–105.
58.Shepherd, PR & Kahn, BB (1999) Glucose transporters and insulin action – implications for insulin resistance and diabetes mellitus. N Engl J Med 341, 248257.
59.Abel, ED, Peroni, O, Kim, JK et al. (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729733.
60.Pérez de Heredia, F, Wood, IS & Trayhurn, P (2009) Acute and chronic hypoxia selectively modulates the expression of glucose transporters (GLUTs) in human adipocytes. Obes Facts 2, Suppl. 2, 39.
61.Chung, S, Lapoint, K, Martinez, K et al. (2006) Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 147, 53405351.
62.Simons, PJ, van den Pangaart, PS, van Roomen, CP et al. (2005) Cytokine-mediated modulation of leptin and adiponectin secretion during in vitro adipogenesis: evidence that tumor necrosis factor-alpha- and interleukin-1beta-treated human preadipocytes are potent leptin producers. Cytokine 32, 94–103.
63.Yun, Z, Maecker, HL, Johnson, RS et al. (2002) Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell 2, 331341.
64.Carriere, A, Carmona, MC, Fernandez, Y et al. (2004) Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. J Biol Chem 279, 4046240469.
65.Kim, KH, Song, MJ, Chung, J et al. (2005) Hypoxia inhibits adipocyte differentiation in a HDAC-independent manner. Biochem Biophys Res Commun 333, 11781184.
66.Zhou, S, Lechpammer, S, Greenberger, JS et al. (2005) Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling. J Biol Chem 280, 2268822696.
67.Wang, B, Wood, IS & Trayhurn, P (2008) Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes. J Endocrinol 198, 127134.
68.Sagawa, N, Yura, S, Itoh, H et al. (2002) Role of leptin in pregnancy-a review. Placenta 23, Suppl. A, S80S86.
69.Lewis, JS, Lee, JA, Underwood, JC et al. (1999) Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukoc Biol 66, 889900.
70.Oda, T, Hirota, K, Nishi, K et al. (2006) Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am J Physiol Cell Physiol 291, C104C113.
71.Rausch, ME, Weisberg, S, Vardhana, P et al. (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32, 451463.
72.Skurk, T, Herder, C, Kraft, I et al. (2005) Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146, 10061011.
73.Trayhurn, P, Wang, B & Wood, IS (2008) Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 100, 227235.
74.Gruen, ML, Hao, M, Piston, DW et al. (2007) Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. Am J Physiol Cell Physiol 293, C1481C1488.
75.Trayhurn, P & Wood, IS (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33, 10781081.
76.Constant, VA, Gagnon, A, Landry, A et al. (2006) Macrophage-conditioned medium inhibits the differentiation of 3T3-L1 and human abdominal preadipocytes. Diabetologia 49, 14021411.
77.Lacasa, D, Taleb, S, Keophiphath, M et al. (2007) Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. Endocrinology 148, 868877.
78.Permana, PA, Menge, C & Reaven, PD (2006) Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun 341, 507514.
79.Permana, PA, Zhang, W, Wabitsch, M et al. (2009) Pioglitazone reduces inflammatory responses of human adipocytes to factors secreted by monocytes/macrophages. Am J Physiol Endocrinol Metab 296, E1076E1084.
80.Houstis, N, Rosen, ED & Lander, ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944948.
81.Gregor, MF & Hotamisligil, GS (2007) Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48, 19051914.
82.Ozcan, U, Cao, Q, Yilmaz, E et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
83.Williams, A & Scharf, SM (2007) Obstructive sleep apnea, cardiovascular disease, and inflammation – is NF-kappaB the key? Sleep Breath 11, 6976.
84.Sheehan, AL, Warren, BF, Gear, MW et al. (1992) Fat-wrapping in Crohn's disease: pathological basis and relevance to surgical practice. Br J Surg 79, 955958.

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed