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Adipose Tissue Vascularization: Its Role in Chronic Inflammation

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Abstract

In obesity, the vascular complication is a result of insulin resistance, such as decreased capillary recruitment in skeletal muscle from endothelial insulin resistance. Recent progress in the study of obesity-associated inflammation suggests that vasculature dysfunction occurs in adipose tissue before insulin resistance. In obesity, capillary density and function fail to meet the demand of adipose tissue growth. The failure leads to microcirculation dysfunction from an impaired blood perfusion, which results in a local hypoxia response in adipose tissue. The hypoxia response in adipocytes and macrophages is a new cellular basis for the chronic inflammation. The obesity-associated inflammation has both positive and negative effects in the body. At the early stage, it amplifies the hypoxia signal to stimulate vasculature remodeling locally, and promotes systemic energy expenditure against obesity. At the late stage, it causes adipose tissue dysfunction for insulin resistance. These points suggest that in obesity, adipose tissue vascularization controls chronic inflammation and influences systemic insulin sensitivity.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140:338–48.

    Article  PubMed  CAS  Google Scholar 

  2. Shoelson SE, Goldfine AB. Getting away from glucose: fanning the flames of obesity-induced inflammation. Nat Med. 2009;15:373–4.

    Article  PubMed  CAS  Google Scholar 

  3. Gao Z, He Q, Peng B, Chiao PJ, Ye J. Regulation of nuclear translocation of HDAC3 by I{kappa}B{alpha} is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J Biol Chem. 2006;281:4540–7.

    Article  PubMed  CAS  Google Scholar 

  4. Larsen OA, Lassen NA, Quaade F. Blood flow through human adipose tissue determined with radioactive xenon. Acta Physiol Scand. 1966;66:337–45.

    Article  PubMed  CAS  Google Scholar 

  5. Crandall DL, Goldstein BM, Huggins F, Cervoni P. Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation. Am J Physiol. 1984;247:R46–51.

    PubMed  CAS  Google Scholar 

  6. West DB, Prinz WA, Francendese AA, Greenwood MR. Adipocyte blood flow is decreased in obese Zucker rats. Am J Physiol. 1987;253:R228–233.

    PubMed  CAS  Google Scholar 

  7. Bolinder J, Kerckhoffs DA, Moberg E, Hagstrom-Toft E, Arner P. Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects. Diabetes. 2000;49:797–802.

    Article  PubMed  CAS  Google Scholar 

  8. Kampf C, Bodin B, Kallskog O, Carlsson C, Jansson L. Marked increase in white adipose tissue blood perfusion in the type 2 diabetic GK rat. Diabetes. 2005;54:2620–7.

    Article  PubMed  CAS  Google Scholar 

  9. Jansson PA, Larsson A, Lonnroth PN. Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1998;28:813–8.

    Article  PubMed  CAS  Google Scholar 

  10. Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes. 2002;51:2467–73.

    Article  PubMed  CAS  Google Scholar 

  11. Ye J, Gao Z, Yin J, He H. 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 

  12. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56:901–11.

    Article  PubMed  CAS  Google Scholar 

  13. Kabon B, Nagele A, Reddy D, Eagon C, Fleshman JW, Sessler DI, et al. Obesity decreases perioperative tissue oxygenation. Anesthesiology. 2004;100:274–80.

    Article  PubMed  Google Scholar 

  14. Fleischmann E, Kurz A, Niedermayr M, Schebesta K, Kimberger O, Sessler DI, et al. Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg. 2005;15:813–9.

    Article  PubMed  Google Scholar 

  15. 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 

  16. Bluher M, Wilson-Fritch L, Leszyk J, Laustsen PG, Corvera S, Kahn CR. Role of insulin action and cell size on protein expression patterns in adipocytes. J Biol Chem. 2004;279:31902–9.

    Article  PubMed  Google Scholar 

  17. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes. 2009;33:54–66.

    Article  CAS  Google Scholar 

  18. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 2005;54:2277–86.

    Article  PubMed  CAS  Google Scholar 

  19. Higami Y, Barger JL, Page GP, Allison DB, Smith SR, Prolla TA, et al. Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr. 2006;136:343–52.

    PubMed  CAS  Google Scholar 

  20. 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.

    Google Scholar 

  21. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes. 2009;58:718–25.

    Article  PubMed  CAS  Google Scholar 

  22. Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol. 1998;275:L818–826.

    PubMed  CAS  Google Scholar 

  23. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    PubMed  CAS  Google Scholar 

  24. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

    PubMed  CAS  Google Scholar 

  25. Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, et al. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes. 2005;54:2305–13.

    Article  PubMed  Google Scholar 

  26. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77.

    Article  PubMed  CAS  Google Scholar 

  27. Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes. 2007;56:2242–50.

    Article  PubMed  CAS  Google Scholar 

  28. Cho C-H, Jun Koh Y, Han J, Sung H-K, Jong Lee H, Morisada T, et al. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res. 2007;100:e47–57.

    Article  PubMed  CAS  Google Scholar 

  29. •• Yin J, Gao Z, He Q, Ye J. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab. 2009;296:E333–42. This is the first comprehensive study of hypoxia in the regulation of adipocyte function (insulin signaling, lipolysis, FFA elevation, adipocyte apoptosis, and necrosis). It also provides background information about adipose tissue hypoxia through literature review.

    Article  PubMed  CAS  Google Scholar 

  30. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46:2347–55.

    Article  PubMed  CAS  Google Scholar 

  31. Strissel KJ, Stancheva Z, Miyoshi H, Perfield 2nd JW, DeFuria J, Jick Z, et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007;56:2910–8.

    Article  PubMed  CAS  Google Scholar 

  32. 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;32:451–63.

    Article  CAS  Google Scholar 

  33. Weinberger B, Carbone T, England S, Kleinfeld AM, Hiatt M, Hegyi T. Effects of perinatal hypoxia on serum unbound free fatty acids and lung inflammatory mediators. Biol Neonate. 2001;79:61–6.

    Article  PubMed  CAS  Google Scholar 

  34. 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;2:331–41.

    Article  PubMed  CAS  Google Scholar 

  35. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006;21:521–31.

    Article  PubMed  Google Scholar 

  36. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002;22:7405–16.

    Article  PubMed  CAS  Google Scholar 

  37. Ozcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61.

    Article  PubMed  Google Scholar 

  38. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313:1137–40.

    Article  PubMed  Google Scholar 

  39. Keijer J, van Schothorst EM. Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components. Curr Opin Lipidol. 2008;19:4–10.

    Article  PubMed  CAS  Google Scholar 

  40. Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, 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;341:549–56.

    Article  PubMed  CAS  Google Scholar 

  41. Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem. 2002;277:34601–9.

    Article  PubMed  CAS  Google Scholar 

  42. Grosfeld A, Andre J, Hauguel-De Mouzon S, Berra E, Pouyssegur J, Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J Biol Chem. 2002;277:42953–7.

    Article  PubMed  CAS  Google Scholar 

  43. 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;198:127–34.

    Article  PubMed  CAS  Google Scholar 

  44. Yasumasu T, Takahara K, Nakashima Y. Hypoxia inhibits leptin production by cultured rat adipocytes. Obes Res. 2002;10:128.

    Article  PubMed  Google Scholar 

  45. Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab. 2008;295:E313–22.

    Article  PubMed  CAS  Google Scholar 

  46. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. HIF 1 alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29:4467–83.

    Article  PubMed  CAS  Google Scholar 

  47. Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, Tran KV, Straubhaar J, Nicoloro S, Czech MP, Thompson M, Perugini RA, Corvera S: Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation. 2011;123:186–194.

    Google Scholar 

  48. Goossens GH, McQuaid SE, Dennis AL, van Baak MA, Blaak EE, Frayn KN, et al. Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans. J Physiol. 2006;571:451–60.

    Article  PubMed  CAS  Google Scholar 

  49. Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Krishna V, et al. Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res. 2003;93:e88–97.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  51. Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, et al. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes. 2007;56:1517–26.

    Article  PubMed  CAS  Google Scholar 

  52. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Yagui K, Saito Y. Roles of degree of fat deposition and its localization on VEGF expression in adipocytes. Am J Physiol Endocrinol Metab. 2005;288:E1128–1136.

    Article  PubMed  CAS  Google Scholar 

  53. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia. 2003;46:1483–8.

    Article  PubMed  CAS  Google Scholar 

  54. Ledoux S, Queguiner I, Msika S, Calderari S, Rufat P, Gasc JM, et al. Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity. Diabetes. 2008;57:3247–57.

    Article  PubMed  CAS  Google Scholar 

  55. Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation. J Immunol. 2005;175:6257–63.

    PubMed  CAS  Google Scholar 

  56. •• Ye J, Keller J. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging. 2010;2:361–8. This is a review article that provides comprehensive information about inflammation in the regulation of energy metabolism. The positive activity of inflammation is emphasized for the first time in obesity in this article.

    PubMed  CAS  Google Scholar 

  57. Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Mynatt R, et al. Uncoupling of inflammation and insulin resistance by NF-kB in transgenic mice through induction of energy expenditure. J Biol Chem. 2010;285:4637–44.

    Article  PubMed  CAS  Google Scholar 

  58. Iiyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O’Doherty RM, Polotsky VY, O’Donnell CP: Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med. 2007;175:851–857.

    Google Scholar 

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Acknowledgements

This manuscript was prepared with support from National Institutes of Health (NIH) funds (DK68036 and DK85495) to J. Ye.

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No potential conflict of interest relevant to this article was reported.

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Authors and Affiliations

  1. Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA

    Jianping Ye

  2. Antioxidant and Gene Regulation Lab, PBRC/LSU, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Jianping Ye

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Ye, J. Adipose Tissue Vascularization: Its Role in Chronic Inflammation. Curr Diab Rep 11, 203–210 (2011). https://doi.org/10.1007/s11892-011-0183-1

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