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The microcirculation in adipose tissue inflammation

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Abstract

In most humans, obesity is associated with a chronic low-grade inflammatory reaction occurring in several organ tissues, including the adipose tissue. Infiltration of bone marrow derived leukocytes (granulocytes, monocytes, lymphocytes) into expanding adipose depots appears to be an integral component of inflammation in obesity. Circulating leukocytes invade organ tissues mainly through post-capillary venules in the microcirculation. The endothelium of the post-capillary venules acts as a gatekeeper to leukocyte adhesion and extravasation by displacing on its luminal surface adhesion molecules that bind the adhesive receptors expressed on circulating leukocytes. Several studies investigating the impact of obesity on the microcirculation have demonstrated the occurrence of microvascular dysfunction in experimental animal model of obesity, as well as in obese humans. To date though, working hypotheses and study designs have favored the view that microvascular alterations are secondary to adipose tissue dysfunction. Indeed, a significant amount of data exists in the scientific literature to support the concept that microvascular dysfunction may precede and cause adipose tissue inflammation in obesity. Through review of key published data, this article prospectively presents the concept that in response to nutrients overload the vascular endothelium of the microcirculation acutely activates inflammatory pathways that initiate infiltration of leukocytes in visceral adipose tissue, well before weight gain and overt obesity. The anatomical and physiological heterogeneity of different microcirculations is also discussed toward the understanding of how obesity induces different inflammatory phenotypes in visceral and subcutaneous fat depots.

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References

  1. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood). 2009;28(5):w822–31.

    Article  Google Scholar 

  2. WHO. WHO fact files: ten facts on obesity. http://www.who.int/features/factfiles/obesity/en/index.html (2010).

  3. Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children and adolescents, 2007–2008. JAMA. 2010;303(3):242–9.

    Article  PubMed  CAS  Google Scholar 

  4. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.

    Article  PubMed  CAS  Google Scholar 

  5. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.

    Article  PubMed  CAS  Google Scholar 

  6. Bauer KW, Hearst MO, Earnest AA, French SA, Oakes JM, Harnack LJ. Energy content of U.S. Fast-food restaurant offerings: 14-year trends. Am J Prev Med. 2012;43(5):490–7.

    Article  PubMed  Google Scholar 

  7. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91.

    Article  PubMed  CAS  Google Scholar 

  8. 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(12):1796–808.

    PubMed  CAS  Google Scholar 

  9. Itoh M, Suganami T, Hachiya R, Ogawa Y. Adipose tissue remodeling as homeostatic inflammation. Int J Inflam. 2011;2011:720926.

    PubMed  Google Scholar 

  10. Gersh I, Still MA. Blood vessels in fat tissue. Relation to problems of gas exchange. J Exp Med. 1945;81(2):219–32.

    Article  PubMed  CAS  Google Scholar 

  11. Hausberger FX, Widelitz MM. Distribution of labeled erythrocytes in adipose tissue and muscle in the rat. Am J Physiol. 1963;204:649–52.

    PubMed  CAS  Google Scholar 

  12. Kroeger S. The influence of intravenously administered fat emulsions on the microcirculation of pancreas and mesenteric adipose tissue. Adv Microcirc. 1970;3:1–66.

    Google Scholar 

  13. Lo A, Fuglevand AJ, Secomb TW. Oxygen delivery to skeletal muscle fibers: effects of microvascular unit structure and control mechanisms. Am J Physiol Heart Circ Physiol. 2003;285(3):H955–63.

    PubMed  CAS  Google Scholar 

  14. Davies BS, Beigneux AP, Barnes 2nd RH, Tu Y, Gin P, Weinstein MM, et al. GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries. Cell Metab. 2010;12(1):42–52.

    Article  PubMed  CAS  Google Scholar 

  15. Stremmel W, Pohl L, Ring A, Herrmann T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids. 2001;36(9):981–9.

    Article  PubMed  CAS  Google Scholar 

  16. Mathew M, Tay E, Cusi K. Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol. 2010;9:9.

    Article  PubMed  CAS  Google Scholar 

  17. Sarelius IH, Kuebel JM, Wang J, Huxley VH. Macromolecule permeability of in situ and excised rodent skeletal muscle arterioles and venules. Am J Physiol Heart Circ Physiol. 2006;290(1):H474–80.

    Article  PubMed  CAS  Google Scholar 

  18. Michel CC, Curry FE. Microvascular permeability. Physiol Rev. 1999;79(3):703–61.

    PubMed  CAS  Google Scholar 

  19. Kurose I, Argenbright LW, Anderson DC, Tolley J, Miyasaka M, Harris N, et al. Reperfusion-induced leukocyte adhesion and vascular protein leakage in normal and hypercholesterolemic rats. Am J Physiol. 1997;273(2 Pt 2):H854–60.

    PubMed  CAS  Google Scholar 

  20. Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008;87(5):1219–23.

    Google Scholar 

  21. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116(1):39–48.

    Article  PubMed  Google Scholar 

  22. Jackson CJ, Nguyen M. Human microvascular endothelial cells differ from macrovascular endothelial cells in their expression of matrix metalloproteinases. Int J Biochem Cell Biol. 1997;29(10):1167–77.

    Article  PubMed  CAS  Google Scholar 

  23. Sandow SL, Haddock RE, Hill CE, Chadha PS, Kerr PM, Welsh DG, et al. What’s where and why at a vascular myoendothelial microdomain signalling complex. Clin Exp Pharmacol Physiol. 2009;36(1):67–76.

    Article  PubMed  CAS  Google Scholar 

  24. Ballard K, Malmfors T, Rosell S. Adrenergic innervation and vascular patterns in canine adipose tissue. Microvasc Res. 1974;8(2):164–71.

    Article  PubMed  CAS  Google Scholar 

  25. Boivin A, Brochu G, Marceau S, Marceau P, Hould FS, Tchernof A. Regional differences in adipose tissue metabolism in obese men. Metabolism. 2007;56(4):533–40.

    Article  PubMed  CAS  Google Scholar 

  26. Jensen MD, Sarr MG, Dumesic DA, Southorn PA, Levine JA. Regional uptake of meal fatty acids in humans. Am J Physiol Endocrinol Metab. 2003;285(6):E1282–8.

    PubMed  CAS  Google Scholar 

  27. Marin P, Lonn L, Andersson B, Oden B, Olbe L, Bengtsson BA, et al. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. J Clin Endocrinol Metab. 1996;81(3):1018–22.

    Article  PubMed  CAS  Google Scholar 

  28. Koutsari C, Ali AH, Mundi MS, Jensen MD. Storage of circulating free fatty acid in adipose tissue of postabsorptive humans: quantitative measures and implications for body fat distribution. Diabetes. 2011;60(8):2032–40.

    Article  PubMed  CAS  Google Scholar 

  29. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97–105.

    Article  PubMed  CAS  Google Scholar 

  30. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    Article  PubMed  CAS  Google Scholar 

  31. Barbarroja N, Lopez-Pedrera R, Mayas MD, Garcia-Fuentes E, Garrido-Sanchez L, Macias-Gonzalez M, et al. The obese healthy paradox: is inflammation the answer? Biochem J. 2010;430(1):141–9.

    Google Scholar 

  32. Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, et al. Insulin-sensitive obesity. American journal of physiology. Endocrinol Metab. 2010;299(3):E506–15.

    Google Scholar 

  33. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298(4):E751–60.

    Google Scholar 

  34. 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(12):1821–30.

    PubMed  CAS  Google Scholar 

  35. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111–9.

    PubMed  CAS  Google Scholar 

  36. De Boer MP, Meijer RI, Wijnstok NJ, Jonk AM, Houben AJ, Stehouwer CD, et al. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation. 2012;19(1):5–18.

    Article  PubMed  CAS  Google Scholar 

  37. Ye J. Adipose tissue vascularization: its role in chronic inflammation. Curr Diab Rep. 2011;11(3):203–10.

    Article  PubMed  CAS  Google Scholar 

  38. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29(16):4467–83.

    Google Scholar 

  39. Ellis A, Cheng ZJ, Li Y, Jiang YF, Yang J, Pannirselvam M, et al. Effects of a Western diet versus high glucose on endothelium-dependent relaxation in murine micro- and macro-vasculature. Eur J Pharmacol. 2008;601(1–3):111–7.

    Article  PubMed  CAS  Google Scholar 

  40. Booth G, Stalker TJ, Lefer AM, Scalia R. Mechanisms of amelioration of glucose-induced endothelial dysfunction following inhibition of protein kinase C in vivo. Diabetes. 2002;51(5):1556–64.

    Article  PubMed  CAS  Google Scholar 

  41. Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest. 2010;120(10):3466–79.

    Article  PubMed  CAS  Google Scholar 

  42. Shimabukuro M, Chinen I, Higa N, Takasu N, Yamakawa K, Ueda S. Effects of dietary composition on postprandial endothelial function and adiponectin concentrations in healthy humans: a crossover controlled study. Am J Clin Nutr. 2007;86(4):923–8.

    PubMed  CAS  Google Scholar 

  43. Ley K. Leukocyte recruitment as seen by intravital microscopy. In: Ley K, editor. Physiology of inflammation. New York: Oxford University Press; 2001. p. 303–37.

    Google Scholar 

  44. Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am J Hypertens. 2001;14(6 Pt 2):44S–54.

    Article  PubMed  CAS  Google Scholar 

  45. Jung U, Ley K. Regulation of E-selectin, P-selectin, and intercellular adhesion molecule 1 expression in mouse cremaster muscle vasculature. Microcirculation. 1997;4(2):311–9.

    Article  PubMed  CAS  Google Scholar 

  46. Klein LM, Lavker RM, Matis WL, Murphy GF. Degranulation of human mast cells induces an endothelial antigen central to leukocyte adhesion. Proc Natl Acad Sci U S A. 1989;86(22):8972–6.

    Article  PubMed  CAS  Google Scholar 

  47. Gotsch U, Jager U, Dominis M, Vestweber D. Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-alpha in vivo. Cell Adhes Commun. 1994;2(1):7–14.

    Article  PubMed  CAS  Google Scholar 

  48. Fries JW, Williams AJ, Atkins RC, Newman W, Lipscomb MF, Collins T. Expression of VCAM-1 and E-selectin in an in vivo model of endothelial activation. Am J Pathol. 1993;143(3):725–37.

    PubMed  CAS  Google Scholar 

  49. Zweifach BW, Lipowsky HH. Pressure-flow relations in blood and lymph microcirculation. In: Renkin EM, Michel CC, editors. Handbook of physiology. The cardiovascular system: microcirculation. Bethesda: American Physiological Society; 1984. p. 251–307.

    Google Scholar 

  50. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012.

  51. Lorant DE, Topham MK, Whatley RE, McEver RP, McIntyre TM, Prescott SM, et al. Inflammatory roles of P-selectin. J Clin Invest. 1993;92(2):559–70.

    Article  PubMed  CAS  Google Scholar 

  52. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J. 1995;9(10):899–909.

    PubMed  CAS  Google Scholar 

  53. Russo HM, Wickenheiser KJ, Luo W, Ohman MK, Franchi L, Wright AP, et al. P-selectin glycoprotein ligand-1 regulates adhesive properties of the endothelium and leukocyte trafficking into adipose tissue. Circ Res. 2010;107(3):388–97.

    Google Scholar 

  54. Sato C, Shikata K, Hirota D, Sasaki M, Nishishita S, Miyamoto S, et al. P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance. Diabetes. 2011;60(1):189–99.

    Google Scholar 

  55. Zarbock A, Ley K, McEver RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood. 2011;118(26):6743–51.

    Article  PubMed  CAS  Google Scholar 

  56. Broijersen A, Karpe F, Hamsten A, Goodall AH, Hjemdahl P. Alimentary lipemia enhances the membrane expression of platelet P-selectin without affecting other markers of platelet activation. Atherosclerosis. 1998;137(1):107–13.

    Google Scholar 

  57. Kalsch T, Elmas E, Nguyen XD, Kralev S, Leweling H, Kluter H, et al. Effects of alimentary lipemia and inflammation on platelet CD40-ligand. Thromb Res. 2007;120(5):703–8.

    Google Scholar 

  58. Schneider DJ, Hardison RM, Lopes N, Sobel BE, Brooks MM. Association between increased platelet P-selectin expression and obesity in patients with type 2 diabetes: a BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) substudy. Diabetes Care. 2009;32(5):944–9.

    Article  PubMed  CAS  Google Scholar 

  59. De Pergola G, Pannacciulli N, Coviello M, Scarangella A, Di Roma P, Caringella M, et al. sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors. Nutr, Metab, Cardiovasc Dis: NMCD. 2008;18(3):227–32.

    Article  CAS  Google Scholar 

  60. Gallistl S, Sudi KM, Borkenstein M, Weinhandl G, Zotter H, Muntean W. Correlation between cholesterol, soluble P-selectin, and D-dimer in obese children and adolescents. Blood Coagul Fibrinolysis. 2000;11(8):755–60.

    Article  PubMed  CAS  Google Scholar 

  61. Kato H, Kashiwagi H, Shiraga M, Tadokoro S, Kamae T, Ujiie H, et al. Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol. 2006;26(1):224–30.

    Article  PubMed  CAS  Google Scholar 

  62. Johnston GI, Cook RG, McEver RP. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation. Cell. 1989;56(6):1033–44.

    Article  PubMed  CAS  Google Scholar 

  63. Ichimura H, Parthasarathi K, Quadri S, Issekutz AC, Bhattacharya J. Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. J Clin Invest. 2003;111(5):691–9.

    PubMed  CAS  Google Scholar 

  64. Takano M, Meneshian A, Sheikh E, Yamakawa Y, Wilkins KB, Hopkins EA, et al. Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation. Am J Physiol Heart Circ Physiol. 2002;283(5):H2054–61.

    PubMed  CAS  Google Scholar 

  65. Matsushita K, Morrell CN, Cambien B, Yang SX, Yamakuchi M, Bao C, et al. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell. 2003;115(2):139–50.

    Article  PubMed  CAS  Google Scholar 

  66. Davenpeck KL, Gauthier TW, Lefer AM. Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology. 1994;107(4):1050–8.

    PubMed  CAS  Google Scholar 

  67. Ahluwalia A, Foster P, Scotland RS, McLean PG, Mathur A, Perretti M, et al. Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci U S A. 2004;101(5):1386–91.

    Article  PubMed  CAS  Google Scholar 

  68. Fisslthaler B, Fleming I. Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res. 2009;105(2):114–27.

    Google Scholar 

  69. Lindholm CR, Ertel RL, Bauwens JD, Schmuck EG, Mulligan JD, Saupe KW. A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. J Physiol Biochem 2012.

  70. Wu Y, Song P, Xu J, Zhang M, Zou MH. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem. 2007;282(13):9777–88.

    Article  PubMed  CAS  Google Scholar 

  71. Mugabo Y, Mukaneza Y, Renier G. Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction. Metab Clin Exp. 2011;60(5):640–8.

    Google Scholar 

  72. Koeffler HP, Ranyard J, Pertcheck M. Myeloperoxidase: its structure and expression during myeloid differentiation. Blood. 1985;65(2):484–91.

    PubMed  CAS  Google Scholar 

  73. Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009;175(4):1473–82.

    Article  PubMed  CAS  Google Scholar 

  74. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008;49(9):1894–903.

    Article  PubMed  CAS  Google Scholar 

  75. Rossmann C, Rauh A, Hammer A, Windischhofer W, Zirkl S, Sattler W, et al. Hypochlorite-modified high-density lipoprotein promotes induction of HO-1 in endothelial cells via activation of p42/44 MAPK and zinc finger transcription factor Egr-1. Arch Biochem Biophys. 2011;509(1):16–25.

    Google Scholar 

  76. Spallarossa P, Garibaldi S, Barisione C, Ghigliotti G, Altieri P, Tracchi I, et al. Postprandial serum induces apoptosis in endothelial cells: Role of polymorphonuclear-derived myeloperoxidase and metalloproteinase-9 activity. Atherosclerosis. 2008;198(2):458–67.

    Article  PubMed  CAS  Google Scholar 

  77. Malle E, Furtmuller PG, Sattler W, Obinger C. Myeloperoxidase: a target for new drug development? Br J Pharmacol. 2007;152(6):838–54.

    Google Scholar 

  78. Shore SA, Terry RD, Flynt L, Xu A, Hug C. Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol. 2006;118(2):389–95.

    Google Scholar 

  79. Liu M, Liu F. Transcriptional and post-translational regulation of adiponectin. Biochem J. 2010;425(1):41–52.

    Google Scholar 

  80. Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, et al. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest. 2007;117(6):1718–26.

    Article  PubMed  CAS  Google Scholar 

  81. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem. 2003;278(45):45021–6.

    Article  PubMed  CAS  Google Scholar 

  82. Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, et al. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes. 2005;54(12):3358–70.

    Article  PubMed  CAS  Google Scholar 

  83. Trevaskis JL, Gawronska-Kozak B, Sutton GM, McNeil M, Stephens JM, Smith SR, et al. Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice. Obesity (Silver Spring). 2007;15(11):2664–72.

    Article  CAS  Google Scholar 

  84. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621–37.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from The American Diabetes Association and NIDDK grant # R01DK64344

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Scalia, R. The microcirculation in adipose tissue inflammation. Rev Endocr Metab Disord 14, 69–76 (2013). https://doi.org/10.1007/s11154-013-9236-x

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