Skip to main content
×
×
Home

Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?

  • Paul Trayhurn (a1), Bohan Wang (a1) and I. Stuart Wood (a1)
Abstract

White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-α, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr92, 347–355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1α, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome.

  • 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.

      Hypoxia in adipose tissue: a basis for the dysregulation of tissue function 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 Dropbox account. Find out more about sending content to Dropbox.

      Hypoxia in adipose tissue: a basis for the dysregulation of tissue function 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 Google Drive account. Find out more about sending content to Google Drive.

      Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?
      Available formats
      ×
Copyright
Corresponding author
*Corresponding author: Professor Paul Trayhurn, fax +44 151 706 5802, email p.trayhurn@liverpool.ac.uk
References
Hide All
1Trayhurn P & Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60, 329339.
2Rajala MW & Scherer PE (2003) The adipocyte – at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144, 37653773.
3Kershaw EE & Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89, 25482556.
4Trayhurn P & Wood IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92, 347355.
5Rosen ED & Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444, 847853.
6Zhang YY, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM (1994) Positional cloning of the mouse obese gene and its human homolog. Nature 372, 425432.
7Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR & Spiegelman BM (1987) Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237, 402405.
8Flier JS, Cook KS, Usher P & Spiegelman BM (1987) Severely impaired adipsin expression in genetic and acquired obesity. Science 237, 405408.
9Hotamisligil GS, Shargill NS & Spiegelman BM (1993) Adipose expression of tumor necrosis factor-α – direct role in obesity-linked insulin resistance. Science 259, 8791.
10Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444, 860867.
11Wellen KE & Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115, 11111119.
12Arita Y, Kihara S, Ouchi N, et al. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257, 7983.
13Xu 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.
14Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL & Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 17961808.
15Yudkin JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes 27, Suppl. 3, S25S28.
16Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH & Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
17Gregor MF & Hotamisligil GS (2007) Adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48, 19051914.
18Houstis N, Rosen ED & Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944948.
19Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A & Wouters BG (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2α. Mol Cell Biol 22, 74057416.
20Carriere A, Carmona M-C, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L & Casteilla L (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.
21Lolmède K, Durand de Saint Front V, Galitzky J, Lafontan M & Bouloumié A (2003) Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes 27, 11871195.
22Virtanen KA, Lonnroth P, Parkkola R, et al. (2002) Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab 87, 39023910.
23Kabon B, Nagele A, Reddy D, Eagon C, Fleshman JW, Sessler DI & Kurz A (2004) Obesity decreases perioperative tissue oxygenation. Anesthesiology 100, 274280.
24Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LKM & Frayn KN (2002) Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 51, 24672473.
25Skurk T, Alberti-Huber C, Herder C & Hauner H (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92, 10231033.
26Brahimi-Horn MC & Pouysségur J (2007) Oxygen, a source of life and stress. FEBS Lett 581, 35823591.
27Folkman J, Hahnfeldt P & Hlatky L (2000) Cancer: looking outside the genome. Nat Rev Mol Cell Biol 1, 7679.
28Gatenby RA & Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4, 891899.
29Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721732.
30Erecinska M & Silver IA (2001) Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 128, 263276.
31Fleischmann E, Kurz A, Niedermayr M, Schebesta K, Kimberger O, Sessler DI, Kabon B & Prager G (2005) Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg 15, 813819.
32Di Girolamo M, Skinner NS Jr, Hanley HG & Sachs RG (1971) Relationship of adipose tissue blood flow to fat cell size and number. Am J Physiol 220, 932937.
33Thurlby PL & Trayhurn P (1980) Regional blood flow in genetically obese (ob/ob) mice: the importance of brown adipose tissue to the reduced energy expenditure on non-shivering thermogenesis. Pflügers Arch 385, 193201.
34West DB, Prinz WA, Francendese AA & Greenwood MRC (1987) Adipocyte blood flow is decreased in obese Zucker rats. Am J Physiol Reg Integr Comp Physiol 253, R228R233.
35Semenza GL (2001) HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13, 167171.
36Höpfl G, Ogunshola O & Gassmann M (2004) HIFs and tumors – causes and consequences. Am J Physiol Reg Integr Comp Physiol 286, R608R623.
37Lopez-Barneo J, del Toro R, Levitsky KL, Chiara MD & Ortega-Saenz P (2004) Regulation of oxygen sensing by ion channels. J Appl Physiol 96, 11871195.
38Cummins EP & Taylor CT (2005) Hypoxia-responsive transcription factors. Pflügers Arch 450, 363371.
39Rocha S (2007) Gene regulation under low oxygen: holding your breath for transcription. Trends Biochem Sci 32, 389397.
40Ye J, Gao Z, Yin J & He Q (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.
41Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG Jr (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464468.
42Jaakkola P, Mole DR, Tian YM, et al. (2001) Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468472.
43Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE & Lodish HF (1985) Sequence and structure of a human glucose transporter. Science 229, 941945.
44Hosogai N, Fukuhara A, Oshima K, et al. (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901911.
45Rausch ME, Weisberg S, Vardhana P & Tortoriello DV (2007) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) (Epublication ahead of print version 25 September 2007).
46Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM, Ailhaud G & Dani C (1996) Expression of ob gene in adipose-cells – regulation by insulin. J Biol Chem 271, 23652368.
47Fasshauer M, Klein J, Neumann S, Eszlinger M & Paschke R (2001) Adiponectin gene expression is inhibited by β-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett 507, 142146.
48Trayhurn P, Duncan JS, Hoggard N & Rayner DV (1998) Regulation of leptin production: a dominant role for the sympathetic nervous system? Proc Nutr Soc 57, 413419.
49Chen B, Lam KSL, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RL, Zhang J & Xu A (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.
50Segawa K, Fukuhara A, Hosogai N, et al. (2006) Visfatin in adipocytes is upregulated by hypoxia through HIF1α-dependent mechanism. Biochem Biophys Res Commun 349, 875882.
51Zhang QX, Magovern CJ, Mack CA, Budenbender KT, Ko W & Rosengart TK (1997) Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis. J Surg Res 67, 147154.
52Wang B, Wood IS & Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflügers Arch 455, 479492.
53Bae S-K, Kim S-R, Kim JG, Kim JY, Koo TH, Jang H-O, Yun I, Yoo M-A & Bae M-K (2006) Hypoxic induction of human visfatin gene is directly mediated by hypoxia-inducible factor-1. FEBS Lett 580, 41054113.
54Ronkainen VP, Ronkainen JJ, Hanninen SL, Leskinen H, Ruas JL, Pereira T, Poellinger L, Vuolteenaho O & Tavi P (2007) Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. FASEB J 21, 18211830.
55Glassford AJ, Yue P, Sheikh AY, Chun HJ, Zarafshar S, Chan DA, Reaven GM, Quertermous T & Tsao PS (2007) HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes. Am J Physiol Endocrinol Metab 293, E1590E1596.
56Cancello R, Henegar C, Viguerie N, et al. (2005) Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54, 22772286.
57Wang 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.
58Do MS, Nam SY, Hong SE, Kim KW, Duncan JS, Beattie JH & Trayhurn P (2002) Metallothionein gene expression in human adipose tissue from lean and obese subjects. Horm Metab Res 34, 348351.
59Tanji K, Irie Y, Uchida Y, Mori F, Satoh K, Mizushima Y & Wakabayashi K (2003) Expression of metallothionein-III induced by hypoxia attenuates hypoxia-induced cell death in vitro. Brain Res 976, 125129.
60Sierra-Honigmann MR, Nath AK, Murakami C, et al. (1998) Biological action of leptin as an angiogenic factor. Science 281, 16831686.
61Bouloumié A, Drexler HCA, Lafontan M & Busse R (1998) Leptin, the product of Ob gene, promotes angiogenesis. Circ Res 83, 10591066.
62Zhu H, Li J, Qin W, Yang Y, He X, Wan D & Gu J (2002) Cloning of a novel gene, ANGPTL4 and the functional study in angiogenesis. Zhonghua Yi Xue Za Zhi 82, 9499.
63Le Jan S, Amy C, Cazes A, et al. (2003) Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 162, 15211528.
64Ouchi N, Kihara S, Arita Y, et al. (1999) Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100, 24732476.
65Ouchi N, Kihara S, Arita Y, et al. (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway. Circulation 102, 12961301.
66Berg AH, Combs TP, Du X, Brownlee M & Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7, 947953.
67Yamauchi T, Kamon J, Waki H, et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7, 941946.
68Yun Z, Maecker HL, Johnson RS & Giaccia AJ (2002) Inhibition of PPARγ 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell 2, 331341.
69Zhou S, Lechpammer S, Greenberger JS & Glowacki J (2005) Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-β/Smad3 signaling. J Biol Chem 280, 2268822696.
70Kim KH, Song MJ, Chung J, Park H & Kim JB (2005) Hypoxia inhibits adipocyte differentiation in a HDAC-independent manner. Biochem Biophys Res Commun 333, 11781184.
71Lin Q, Lee Y-J & Yun Z (2006) Differentiation arrest by hypoxia. J Biol Chem 281, 3067830683.
72Ren H, Cao Y, Zhao Q, et al. (2006) Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions. Biochem Biophys Res Commun 347, 1221.
73Wood IS & Trayhurn P (2003) Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 89, 39.
74Wood 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.
75Wood IS, Wang B, Lorente-Cebrián S & Trayhurn P (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.
76Larsen JJ, Hansen JM, Olsen NV, Galbo H & Dela F (1997) The effect of altitude hypoxia on glucose homeostasis in men. J Physiol 504, 241249.
77Oltmanns KM, Gehring H, Rudolf S, Schultes B, Rook S, Schweiger U, Born J, Fehm HL & Peters A (2004) Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 169, 12311237.
78Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR & O'Donnell CP (2003) Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552, 253264.
79Iiyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O'Doherty RM, Polotsky VY & O'Donnell CP (2007) Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 175, 851857.
80Gulve EA, Ren JM, Marshall BA, Gao J, Hansen PA, Holloszy JO & Mueckler M (1994) Glucose transport activity in skeletal muscles from transgenic mice overexpressing GLUT1. Increased basal transport is associated with a defective response to diverse stimuli that activate GLUT4. J Biol Chem 269, 1836618370.
81Fain JN, Madan AK, Hiler ML, Cheema P & Bahouth SW (2004) Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145, 22732282.
82Fain 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.
83Lewis JS, Lee JA, Underwood JC, Harris AL & Lewis CE (1999) Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukoc Biol 66, 889900.
84Bosco MC, Puppo M, Pastorino S, Mi Z, Melillo G, Massazza S, Rapisarda A & Varesio L (2004) Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages. J Immunol 172, 16811690.
85Oda T, Hirota K, Nishi K, et al. (2006) Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am J Physiol Cell Physiol 291, C104C113.
86Cousin B, Munoz O, Andre M, Fontanilles AM, Dani C, Cousin JL, Laharrague P, Casteilla L & Penicaud L (1999) A role for preadipocytes as macrophage-like cells. FASEB J 13, 305312.
87Gerhardt CC, Romero IA, Cancello R, Camoin L & Strosberg AD (2001) Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 175, 8192.
88Harkins JM, Moustaid-Moussa N, Chung Y-J, Penner KM, Pestka JJ, North CM & Claycombe KJ (2004) Expression of interleukin-6 is greater in preadipocytes than in adipocytes of 3T3-L1 cells and C57BL/6J and ob/ob mice. J Nutr 134, 26732677.
89Skurk T, Herder C, Kraft I, Muller-Scholze S, Hauner H & Kolb H (2005) Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146, 10061011.
90Wang B, Jenkins JR & Trayhurn P (2005) Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α. Am J Physiol Endocrinol Metab 288, E731E740.
91Chung S, LaPoint K, Martinez K, Kennedy A, Boysen Sandberg M & McIntosh MK (2006) Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 147, 53405351.
92Braun RD, Lanzen JL, Snyder SA & Dewhirst MW (2001) Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol 280, H2533H2544.
93Yu DY & Cringle SJ (2005) Retinal degeneration and local oxygen metabolism. Exp Eye Res 80, 745751.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Full text views

Total number of HTML views: 51
Total number of PDF views: 380 *
Loading metrics...

Abstract views

Total abstract views: 684 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st January 2018. This data will be updated every 24 hours.