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Adipose Tissue Hypoxia in Regulation of Angiogenesis and Obesity

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Angiogenesis in Adipose Tissue

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Abstract

Obesity is strongly associated with co-morbidities such as diabetes, hypertension, atherosclerotic cardiovascular disease and stroke, osteoarthritis, depression and certain cancers, notably of the breast, colon, oesophagus, pancreas, endometrium, kidney and gall bladder. For most of these morbidities metabolic abnormalities originating in pathologically expanded adipose tissues play a key etiological role. In obesity, rapid adipose expansion occurs. In many this is linked with local hypoxia, inadequate vascularization and consequent fibrosis. However, some individuals are resilient and less adversely affected by excess fat accumulation. The notion of ‘healthy’ adipose expandability is being proposed and documented in some animal models and in subgroup of obese individuals. Such healthy adipose expansion requires the fine coordination of adipogenesis and angiogenesis (vascular remodelling) to support expansion by providing the oxygen and nutrients necessary for the adipocyte survival and function. If this balance fails adipose tissue fails to respond to any metabolically challenging situation. Here we focus on one of the mechanisms, adipose tissue hypoxia, involved in regulating adiposity and angiogenesis during obesity.

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Abbreviations

ASC:

Adipose stromal cells

AT:

Adipose tissue

BAT:

Brown adipose tissue

DIO:

Diet-induced obesity

FIH:

Factor inhibiting HIF

11β-HSD1:

11β-Hydroxysteroid dehydrogenase type 1

HIF:

Hypoxia-inducible factor

KO:

Knockout

PDGF:

Platelet-derived growth factor

PHD:

Prolyl hydroxylase domain

POMC:

Proopiomelanocortin

WAT:

White adipose tissue

References

  • Amos PJ et al. Hypoxic culture and in vivo inflammatory environments affect the assumption of pericyte characteristics by human adipose and bone marrow progenitor cells. Am J Physiol Cell Physiol. 2011;301:C1378–88.

    Article  PubMed  CAS  Google Scholar 

  • Ahan GO, Brown JM. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle. 2009;8:970–6.

    Article  Google Scholar 

  • Arany Z et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008;451:1008–12.

    Article  PubMed  CAS  Google Scholar 

  • Bluher M et al. Role of insulin action and cell size on protein expression patterns in adipocytes. J Biol Chem. 2004;279:31902–9.

    Article  PubMed  Google Scholar 

  • Bourlier V et al. TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS One. 2012;7:e31274.

    Article  PubMed  CAS  Google Scholar 

  • Cao Y et al. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005; 332(2):370–9.

    Article  PubMed  CAS  Google Scholar 

  • Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest. 2007;117:2362–8.

    Article  PubMed  CAS  Google Scholar 

  • Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov. 2010;9:107–15.

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–95.

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci. 2000;902:249–62.

    Article  PubMed  CAS  Google Scholar 

  • Cockman M et al. Proteomics-based identification of novel factor inhibiting hypoxia-inducible factor (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. Mol Cell Proteomics. 2009;8:535–46.

    Article  PubMed  CAS  Google Scholar 

  • Coleman ML et al. Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J Biol Chem. 2007;282:24027–38.

    Article  PubMed  CAS  Google Scholar 

  • Cramer T et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;113:419.

    Article  CAS  Google Scholar 

  • Dvorak HF et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995;146:1029–39.

    PubMed  CAS  Google Scholar 

  • Elias I et al. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes. 2012;61:1801–13.

    Article  PubMed  CAS  Google Scholar 

  • Epstein A,C et al. C elegans EGLN-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54.

    Article  PubMed  CAS  Google Scholar 

  • Farb MG et al. Artiriolar function in visceral adipose tissue is impaired in human obesity. Arterioscler Thromb Vasc Biol. 2012;32:467–73.

    Article  PubMed  CAS  Google Scholar 

  • Feldser D et al. Reciprocal positive regulation of hypoxia inducible factor 1alpha and insulin growth factor 2. Cancer Res. 1999;59:3915–8.

    PubMed  CAS  Google Scholar 

  • Ferguson JE et al. ASB4 is a hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism. Mol Cell Biol. 2007;27:6407–19.

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–42.

    Article  PubMed  CAS  Google Scholar 

  • Foster DO, Frydman ML. Brown adipose tissue: the dominant site of nonshivering thermogenesis in the rat. Experientia Suppl. 1978;32:147–52.

    Article  PubMed  CAS  Google Scholar 

  • Gealekman O et al. Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation. 2011;123:186–94.

    Article  PubMed  Google Scholar 

  • Girgis CM et al. Novel links between HIFs, type 2 diabetes, and metabolic syndrome. Trends Endocrinol Metab. 2012;23:372–80.

    Article  PubMed  CAS  Google Scholar 

  • Grosfeld A et al. Hypoxia increases leptin expression in human PAZ6 adipose cells. Diabetologia. 2002;45:527–30.

    Article  PubMed  CAS  Google Scholar 

  • Haddad J,J, Land S,C. A non-hypoxic, ROS sensitive pathway mediates TNF-alpha-dependent regulation of HIF-alpha. FEBS Lett. 2001;505:269–74.

    Article  PubMed  CAS  Google Scholar 

  • Halberg N et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29:4467–83.

    Article  PubMed  CAS  Google Scholar 

  • Hausman GJ, Richardson RL. Adipose tissue angiogenesis. J Anim Sci. 2004;82:925–34.

    PubMed  CAS  Google Scholar 

  • He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1alpha: activity in adipose tissue by obesity-associated factors: adipogenesis, insulin and hypoxia. Am J Physiol Endocrinol Metab. 2011;300:E877–85.

    Article  PubMed  CAS  Google Scholar 

  • Helminger G et al. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997;2:177–82.

    Article  Google Scholar 

  • Higgins DF et al. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol. 2004;287:F1223–32.

    Article  PubMed  CAS  Google Scholar 

  • Higgins DF et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;117:3810–20.

    PubMed  CAS  Google Scholar 

  • Hosogai N et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56:901–11.

    Article  PubMed  CAS  Google Scholar 

  • Ivan M et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  PubMed  CAS  Google Scholar 

  • Jaakkola P et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.

    Article  PubMed  CAS  Google Scholar 

  • 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. 2011;60:2484–95.

    Article  PubMed  CAS  Google Scholar 

  • Kabon B et al. Obesity decreases perioperative tissue oxygenation. Anesthesiology. 2004;100:274–80.

    Article  PubMed  Google Scholar 

  • Kahn T et al. Metabolic dysregulation and adipsoe fibrosis: role of collagen VI. Mol Cell Biol. 2009;29:1575–91.

    Article  Google Scholar 

  • Krishnan J et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 2012;26:259–70.

    Article  PubMed  CAS  Google Scholar 

  • Lando D et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia inducible factor. Genes Dev. 2002;16:1466–71.

    Article  PubMed  CAS  Google Scholar 

  • Lee KY et al. The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation. Cell Metab. 2011;14:491–503.

    Article  PubMed  CAS  Google Scholar 

  • Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 2007;67:8429–32.

    Article  PubMed  CAS  Google Scholar 

  • Lin Q et al. Differentiation arrest by hypoxia. J Biol Chem. 2006;281:30678–83.

    Article  PubMed  CAS  Google Scholar 

  • Lolmede K et al. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord. 2003;27:1187–95.

    Article  PubMed  CAS  Google Scholar 

  • Leonard M,O, Godson C, Brady H,R, Taylor C,T. Potentiation of glucocorticoid activity in hypoxia through the glucocorticoid receptor. J Immunol. 2005;174:2250–7.

    PubMed  CAS  Google Scholar 

  • Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15:2675–86.

    Article  PubMed  CAS  Google Scholar 

  • Maumus M et al. Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: influence of fat mass microenvironment and growth. J Clin Endocrinol Metab. 2008;93:4098–106.

    Article  PubMed  CAS  Google Scholar 

  • Maxwell P,H et al. The tumour suppressor protein VHL targets hypoxia inducible factors to oxygen-dependent proteolysis. Nature. 1999;399:271–5.

    Article  PubMed  CAS  Google Scholar 

  • Mazzati D et al. A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes. Arch Physiol Biochem. 2012;118:112–20.

    Article  Google Scholar 

  • 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. 2012;287:4188–97.

    Article  PubMed  CAS  Google Scholar 

  • Morton N,M et al. Novel adipose tissue mediated resistance to diet-induced visceral obesity in 11β-hydroxysteroid dehydrogenase type 1 deficient mice. Diabetes. 2004;53:931–8.

    Article  PubMed  CAS  Google Scholar 

  • Nauk M, Karakioulakis G, Perruchoud A,P, Papakostantinou E, Roth M. Corticosteroids inhibit the expression of vascular endothelial growth factor gene in human vascular smooth cells. Eur J Pharmacol. 1998;341:309–15.

    Article  Google Scholar 

  • Ndubuizu O,I, Tsipis C,P, Li A, LaManna J,C. Hypoxia inducible factor (HIF-1)-independent microvascular angiogenesis in the aged rat brain. Brain Res. 2010;1366:101–9.

    Article  PubMed  CAS  Google Scholar 

  • O’Hara A et al. Microarray analysis identifies matrix metalloproteinases (MMPSs) as key genes whose expression is upregulated in human adipocytes by macrophage-conditioned medium. Plufgers Arch. 2009;458:1103–14.

    Article  Google Scholar 

  • O’Rourke RW et al. Hypoxia-induced inflammatory cytokine secretion in human tissue stromovascular cells. Diabetologia. 2009;54:1480–90.

    Article  Google Scholar 

  • O’Rourke RW et al. Depot-specific differences in inflammatory mediators and a role of NK cells and INF-γ in inflammation in human adipose tissue. Int J Obes (Lond). 2011;33:978–90.

    Article  Google Scholar 

  • Pang C et al. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodelling in obesity. Am J Physiol Endocrinol Metab. 2008;295:E313–22.

    Article  PubMed  CAS  Google Scholar 

  • Pasarica M et al. Reduced adipose tissue oxygenation in human obesity: evidence of rarefaction, macrophage chemotaxis and inflammation without an angiogenic response. Diabetes. 2009;58:718–25.

    Article  PubMed  CAS  Google Scholar 

  • Rahman J et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–8.

    Article  Google Scholar 

  • Rausch M,E, 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;32:451–63.

    Article  CAS  Google Scholar 

  • Regazzetti C et al. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes. 2009;58:95–103.

    Article  PubMed  CAS  Google Scholar 

  • Shimba S, Wada T, Hara S, Tezuka M. EPAS1 promotes adipose differentiation in 3T3-L1 cells. J Biol Chem. 2004;279:40946–53.

    Article  PubMed  CAS  Google Scholar 

  • Small G,R et al. Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc Natl Acad Sci U S A. 2005;102:12165–70.

    Article  PubMed  CAS  Google Scholar 

  • Stockman C et al. Loss of myeloid cell-derived vascular endothelia growth factor accelerates fibrosis. Proc Natl Acad Sci U S A. 2010;107:4329–34.

    Article  Google Scholar 

  • Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094–101.

    Article  PubMed  CAS  Google Scholar 

  • Sun K et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A. 2012;109:5874–9.

    Article  PubMed  CAS  Google Scholar 

  • Tajima R et al. Hypoxic enhancement of type IV collagen secretion accelerates adipose conversion of 3T3-L1 fibroblasts. Biochim Biophys Acta. 2001;1540:179–87.

    Article  PubMed  CAS  Google Scholar 

  • Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347–55.

    Article  PubMed  CAS  Google Scholar 

  • Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza G,L, Van Obberghen E. Insulin stimulates hypoxia inducible factor 1 through phosphatidylinositol 3-kinase/target of rapamacyn-dependent signalling pathway. J Biol Chem. 2002;277:27975–81.

    Article  PubMed  CAS  Google Scholar 

  • Tzouvelekis A et al. Comparative expression profi ling in pulmonary fi brosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. Am J Respir Crit Care Med. 2007; 176(11):1108–19.

    Article  PubMed  Google Scholar 

  • Villaret A et al. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic and inflammatory gene expression and cellular senescence. Diabetes. 2010;59:2755–63.

    Article  PubMed  CAS  Google Scholar 

  • Small G,R et al. Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc Natl Acad Sci U S A. 2005;102:12165–70.

    Article  PubMed  CAS  Google Scholar 

  • Wilkins SE et al. Differences in hydroxylation and binding of Notch and HIF- 1alpha demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1). Int J Biochem Cell Biol. 2009;41:1563–71.

    Article  PubMed  CAS  Google Scholar 

  • Xue Y et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 2009;9:99–109.

    Article  PubMed  CAS  Google Scholar 

  • 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:E1118–28.

    Article  PubMed  CAS  Google Scholar 

  • Yin J et al. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in obesity. Am J Physiol Endocrinol Metab. 2009;296:E333–42.

    Article  PubMed  CAS  Google Scholar 

  • Yung Y,J, Isaac J,S, Lee S, Trepel J, Neckers L. IL-1beta mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J. 2003;17:2115–7.

    Google Scholar 

  • Yun Z, Maecker HL, Johnson RS, Giaccia AJ. 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. 2002;3:331–41.

    Article  Google Scholar 

  • Zhang N et al. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab. 2010a;11:364–78.

    Article  PubMed  CAS  Google Scholar 

  • Zhang J et al. Hypoxia-inducible factor 1 activation from adipose protein 2-cre mediated knockout of von hippel-lindau gene leads to embryonic lethality. Clin Exp Pharmacol Physiol. 2012;39:145–50.

    Article  PubMed  CAS  Google Scholar 

  • Zhang H et al. Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation. PLoS Biol. 2011;9:e1001112.

    Article  PubMed  CAS  Google Scholar 

  • Zhang X et al. Adipose tissue specific inhibition of hypoxia-inducible factor 1α induces obesity and glucose intolerance by impeding energy expenditure in mice. J Biol Chem. 2010b;285:32869–77.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Research Council Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland

    Zoi Michailidou

  2. University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland

    Jonathan R. Seckl

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  1. Zoi Michailidou
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  2. Jonathan R. Seckl
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Correspondence to Zoi Michailidou or Jonathan R. Seckl .

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Editors and Affiliations

  1. Microbiology, Tumor and Cell biology (MT, Karolinska Institutet, Stockholm, Sweden

    Yihai Cao

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Michailidou, Z., Seckl, J.R. (2013). Adipose Tissue Hypoxia in Regulation of Angiogenesis and Obesity. In: Cao, Y. (eds) Angiogenesis in Adipose Tissue. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8069-3_12

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