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Visceral adiposopathy: a vascular perspective

  • Melissa G. Farb and Noyan Gokce EMAIL logo
Published/Copyright: March 6, 2015

Abstract

Obesity has emerged as one of the most critical health care problems globally that is associated with the development of insulin resistance, type 2 diabetes mellitus, metabolic dysfunction and cardiovascular disease. Central adiposity with intra-abdominal deposition of visceral fat, in particular, has been closely linked to cardiometabolic consequences of obesity. Increasing epidemiological, clinical and experimental data suggest that both adipose tissue quantity and perturbations in its quality termed “adiposopathy” contribute to mechanisms of cardiometabolic disease. The current review discusses regional differences in adipose tissue characteristics and highlights profound abnormalities in vascular endothelial function and angiogenesis that are manifest within the visceral adipose tissue milieu of obese individuals. Clinical data demonstrate up-regulation of pro-inflammatory and pro-atherosclerotic mediators in dysfunctional adipose tissue that may support pathological vascular changes not only locally in fat but also in multiple organ systems, including coronary and peripheral circulations, potentially contributing to mechanisms of obesity-related cardiovascular disease.


Corresponding author: Noyan Gokce, MD, Boston Medical Center, 88 East Newton St, D-8, Cardiology, Boston, MA, 02118, USA, Phone: +1-617-638-8968, Fax: +1-617-638-8969, E-mail:

Acknowledgments

Dr. Gokce is supported by National Institutes of Health (NIH) grants HL081587, HL1145675 and HL126141.

Conflict of interest statement

Disclosures: There are no conflicts of interest to disclose.

References

1. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011;378:815–25.10.1016/S0140-6736(11)60814-3Search in Google Scholar

2. Gortmaker SL, Swinburn BA, Levy D, Carter R, Mabry PL, Finegood DT, Huang T, Marsh T, Moodie ML. Changing the future of obesity: science, policy, and action. Lancet 2011;378:838–47.10.1016/S0140-6736(11)60815-5Search in Google Scholar

3. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. J Am Med Assoc 2012;307:491–7.10.1001/jama.2012.39Search in Google Scholar

4. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011;11:85–97.10.1038/nri2921Search in Google Scholar

5. Kitahara CM, Flint AJ, Berrington de GA, Bernstein L, Brotzman M, MacInnis RJ, Moore SC, Robien K, Rosenberg PS, Singh PN, Weiderpass E, Adami HO, Anton-Culver H, Ballard-Barbash R, Buring JE, Freedman DM, Fraser GE, Beane Freeman LE, Gapstur SM, Gaziano JM, Giles GG, Hakansson N, Hoppin JA, Hu FB, Koenig K, Linet MS, Park Y, Patel AV, Purdue MP, Schairer C, Sesso HD, Visvanathan K, White E, Wolk A, Zeleniuch-Jacquotte A, Hartge P. Association between class III obesity (BMI of 40–59 kg/m2) and mortality: a pooled analysis of 20 prospective studies. PLoS Med 2014;11:e1001673.10.1371/journal.pmed.1001673Search in Google Scholar

6. Berrington de GA, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, Moore SC, Tobias GS, nton-Culver H, Freeman LB, Beeson WL, Clipp SL, English DR, Folsom AR, Freedman DM, Giles G, Hakansson N, Henderson KD, Hoffman-Bolton J, Hoppin JA, Koenig KL, Lee IM, Linet MS, Park Y, Pocobelli G, Schatzkin A, Sesso HD, Weiderpass E, Willcox BJ, Wolk A, Zeleniuch-Jacquotte A, Willett WC, Thun MJ. Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010;363:2211–9.10.1056/NEJMoa1000367Search in Google Scholar

7. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ. 2013 AHA/ACC/TOS Guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the obesity society. Circulation 2013;129:S102–38.10.1161/01.cir.0000437739.71477.eeSearch in Google Scholar

8. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083–96.10.1016/S0140-6736(09)60318-4Search in Google Scholar

9. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–7.10.1038/nature05488Search in Google Scholar

10. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006;444:875–80.10.1038/nature05487Search in Google Scholar

11. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–56.10.1210/jc.2004-0395Search in Google Scholar PubMed

12. Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol 2014;63:250–9.10.1016/j.jjcc.2013.11.006Search in Google Scholar PubMed PubMed Central

13. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–808.10.1172/JCI200319246Search in Google Scholar

14. Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res 2007;48:1253–62.10.1194/jlr.R700005-JLR200Search in Google Scholar PubMed PubMed Central

15. Lim S, Meigs JB. Links between ectopic fat and vascular disease in humans. Arterioscler Thromb Vasc Biol 2014;34:1820–6.10.1161/ATVBAHA.114.303035Search in Google Scholar PubMed PubMed Central

16. Britton KA, Fox CS. Ectopic fat depots and cardiovascular disease. Circulation 2011;124:e837–41.10.1161/CIRCULATIONAHA.111.077602Search in Google Scholar PubMed

17. Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating “sick fat” through improving fat function with antidiabetes therapies. Am J Cardiol 2012;110(9 Suppl):4B–12B.10.1016/j.amjcard.2012.08.029Search in Google Scholar PubMed

18. Bays H. Central obesity as a clinical marker of adiposopathy; increased visceral adiposity as a surrogate marker for global fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014;21:345–51.10.1097/MED.0000000000000093Search in Google Scholar PubMed PubMed Central

19. Mathieu P, Boulanger MC, Despres JP. Ectopic visceral fat: a clinical and molecular perspective on the cardiometabolic risk. Rev Endocr Metab Disord 2014;15:289–98.10.1007/s11154-014-9299-3Search in Google Scholar PubMed

20. Bays HE. Adiposopathy is “sick fat” a cardiovascular disease? J Am Coll Cardiol 2011;57:2461–73.10.1016/j.jacc.2011.02.038Search in Google Scholar PubMed

21. Chau YY, Bandiera R, Serrels A, Martinez-Estrada OM, Qing W, Lee M, Slight J, Thornburn A, Berry R, McHaffie S, Stimson RH, Walker BR, Chapuli RM, Schedl A, Hastie N. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol 2014;16:367–75.10.1038/ncb2922Search in Google Scholar PubMed PubMed Central

22. Karastergiou K, Fried SK. Multiple adipose depots increase cardiovascular risk via local and systemic effects. Curr Atheroscler Rep 2013;15:361.10.1007/s11883-013-0361-5Search in Google Scholar PubMed PubMed Central

23. Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med 2013;34:1–11.10.1016/j.mam.2012.10.001Search in Google Scholar PubMed PubMed Central

24. Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, Forse RA, Chinnappan D, Martin-Ruiz C, von ZT, Kirkland JL. Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 2006;55:2571–8.10.2337/db06-0540Search in Google Scholar PubMed

25. Virtanen KA, Lonnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, Tolvanen T, Knuuti J, Ronnemaa T, Huupponen R, Nuutila P. Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab 2002;87:3902–10.10.1210/jcem.87.8.8761Search in Google Scholar PubMed

26. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010;11:11–8.10.1111/j.1467-789X.2009.00623.xSearch in Google Scholar PubMed

27. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. 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 2004;145:2273–82.10.1210/en.2003-1336Search in Google Scholar PubMed

28. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 2007;56:1010–3.10.2337/db06-1656Search in Google Scholar PubMed

29. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest 2004;113:1582–8.10.1172/JCI21047Search in Google Scholar PubMed PubMed Central

30. Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract 2005;69:29–35.10.1016/j.diabres.2004.11.007Search in Google Scholar PubMed

31. Rexrode KM, Pradhan A, Manson JE, Buring JE, Ridker PM. Relationship of total and abdominal adiposity with CRP and IL-6 in women. Ann Epidemiol 2003;13:674–82.10.1016/S1047-2797(03)00053-XSearch in Google Scholar

32. Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 2002;51:3391–9.10.2337/diabetes.51.12.3391Search in Google Scholar

33. Tsigos C, Kyrou I, Chala E, Tsapogas P, Stavridis JC, Raptis SA, Katsilambros N. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metabolism 1999;48:1332–5.10.1016/S0026-0495(99)90277-9Search in Google Scholar

34. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. J Am Med Assoc 1999;282:2131–5.10.1001/jama.282.22.2131Search in Google Scholar PubMed

35. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. J Am Med Assoc 2001;286:327–34.10.1001/jama.286.3.327Search in Google Scholar PubMed

36. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–72.10.1161/01.CIR.101.15.1767Search in Google Scholar PubMed

37. Ford ES. C-reactive protein concentration and cardiovascular disease risk factors in children: findings from the National Health and Nutrition Examination Survey 1999–2000. Circulation 2003;108:1053–8.10.1161/01.CIR.0000080913.81393.B8Search in Google Scholar PubMed

38. Kapiotis S, Holzer G, Schaller G, Haumer M, Widhalm H, Weghuber D, Jilma B, Roggla G, Wolzt M, Widhalm K, Wagner OF. A proinflammatory state is detectable in obese children and is accompanied by functional and morphological vascular changes. Arterioscler Thromb Vasc Biol 2006;26:2541–6.10.1161/01.ATV.0000245795.08139.70Search in Google Scholar PubMed

39. Skinner AC, Steiner MJ, Henderson FW, Perrin EM. Multiple markers of inflammation and weight status: cross-sectional analyses throughout childhood. Pediatrics 2010;125:e801–9.10.1542/peds.2009-2182Search in Google Scholar PubMed PubMed Central

40. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Low-grade systemic inflammation in overweight children. Pediatrics 2001;107:E13.10.1542/peds.107.1.e13Search in Google Scholar PubMed

41. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;327:1350–5.10.1056/NEJM199211053271904Search in Google Scholar PubMed

42. Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 2008;14:1225–30.10.2174/138161208784246153Search in Google Scholar PubMed

43. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007;56:16–23.10.2337/db06-1076Search in Google Scholar PubMed

44. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821–30.10.1172/JCI200319451Search in Google Scholar

45. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003;112:1785–8.10.1172/JCI20514Search in Google Scholar PubMed PubMed Central

46. Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 2009;94:4619–23.10.1210/jc.2009-0925Search in Google Scholar PubMed

47. Farb MG, Ganley-Leal L, Mott M, Liang Y, Ercan B, Widlansky ME, Bigornia SJ, Fiscale AJ, Apovian CM, Carmine B, Hess DT, Vita JA, Gokce N. Arteriolar function in visceral adipose tissue is impaired in human obesity. Arterioscler Thromb Vasc Biol 2012;32:467–73.10.1161/ATVBAHA.111.235846Search in Google Scholar PubMed PubMed Central

48. Apovian CM, Bigornia S, Mott M, Meyers MR, Ulloor J, Gagua M, McDonnell M, Hess D, Joseph L, Gokce N. Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol 2008;28:1654–9.10.1161/ATVBAHA.108.170316Search in Google Scholar PubMed PubMed Central

49. Bigornia SJ, Farb MG, Mott MM, Hess DT, Carmine B, Fiscale A, Joseph L, Apovian CM, Gokce N. Relation of depot-specific adipose inflammation to insulin resistance in human obesity. Nutr Diabetes 2012;2:e30.10.1038/nutd.2012.3Search in Google Scholar PubMed PubMed Central

50. Farb MG, Bigornia S, Mott M, Tanriverdi K, Morin KM, Freedman JE, Joseph L, Hess DT, Apovian CM, Vita JA, Gokce N. Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity. J Am Coll Cardiol 2011;58:232–7.10.1016/j.jacc.2011.01.051Search in Google Scholar PubMed PubMed Central

51. Le KA, Mahurkar S, Alderete TL, Hasson RE, Adam TC, Kim JS, Beale E, Xie C, Greenberg AS, Allayee H, Goran MI. Subcutaneous adipose tissue macrophage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-kappaB stress pathway. Diabetes 2011;60:2802–9.10.2337/db10-1263Search in Google Scholar

52. McLaughlin T, Lamendola C, Liu A, Abbasi F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol Metab 2011;96:E1756–60.10.1210/jc.2011-0615Search in Google Scholar

53. Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, Keaney JF, Jr., Meigs JB, Lipinska I, Kathiresan S, Murabito JM, O’Donnell CJ, Benjamin EJ, Fox CS. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 2007;116:1234–41.10.1161/CIRCULATIONAHA.107.710509Search in Google Scholar

54. Alvehus M, Buren J, Sjostrom M, Goedecke J, Olsson T. The human visceral fat depot has a unique inflammatory profile. Obesity (Silver Spring) 2010;18:879–83.10.1038/oby.2010.22Search in Google Scholar

55. Farb MG, Tiwari S, Karki S, Ngo DT, Carmine B, Hess DT, Zuriaga MA, Walsh K, Fetterman JL, Hamburg NM, Vita JA, Apovian CM, Gokce N. Cyclooxygenase inhibition improves endothelial vasomotor dysfunction of visceral adipose arterioles in human obesity. Obesity (Silver Spring) 2014;22:349–55.10.1002/oby.20505Search in Google Scholar

56. Fuster JJ, Zuriaga MA, Thi-Minh ND, Farb MG, Aprahamian T, Yamaguchi TP, Gokce N, Walsh K. Non-canonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 2014; Epub ahead of print.10.1016/j.atherosclerosis.2014.05.041Search in Google Scholar

57. 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;123:186–94.10.1161/CIRCULATIONAHA.110.970145Search in Google Scholar

58. Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schon MR, Stumvoll M, Bluher M, Kahn BB. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab 2007;6:79–87.10.1016/j.cmet.2007.06.002Search in Google Scholar

59. Lafontan M, Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 2003;24:276–83.10.1016/S0165-6147(03)00132-9Search in Google Scholar

60. Ledoux S, Queguiner I, Msika S, Calderari S, Rufat P, Gasc JM, Corvol P, Larger E. Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity. Diabetes 2008;57:3247–57.10.2337/db07-1812Search in Google Scholar PubMed PubMed Central

61. Samaras K, Botelho NK, Chisholm DJ, Lord RV. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity (Silver Spring) 2010;18:884–9.10.1038/oby.2009.443Search in Google Scholar

62. Xu XJ, Gauthier MS, Hess DT, Apovian CM, Cacicedo JM, Gokce N, Farb M, Valentine RJ, Ruderman NB. Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res 2012;53:792–801.10.1194/jlr.P022905Search in Google Scholar

63. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847–50.10.1210/jc.83.3.847Search in Google Scholar

64. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129–38.10.1016/j.jacc.2009.09.009Search in Google Scholar

65. Gokce N, Keaney JF, Jr., Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003;41:1769–75.10.1016/S0735-1097(03)00333-4Search in Google Scholar

66. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, Saito Y, Kawabata K, Sano K, Kobayashi T, Yano T, Nakamura K, Kugiyama K. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol 2009;53:323–30.10.1016/j.jacc.2008.08.074Search in Google Scholar

67. Widlansky ME, Gokce N, Keaney JF, Jr., Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149–60.10.1016/S0735-1097(03)00994-XSearch in Google Scholar

68. Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation 2011;123:163–9.10.1161/CIRCULATIONAHA.110.953653Search in Google Scholar PubMed

69. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007;115:1285–95.10.1161/CIRCULATIONAHA.106.652859Search in Google Scholar PubMed

70. Gokce N. Clinical assessment of endothelial function: ready for prime time? Circ Cardiovasc Imaging 2011;4:348–50.10.1161/CIRCIMAGING.111.966218Search in Google Scholar PubMed PubMed Central

71. Hamburg NM, Larson MG, Vita JA, Vasan RS, Keyes MJ, Widlansky ME, Fox CS, Mitchell GF, Levy D, Meigs JB, Benjamin EJ. Metabolic syndrome, insulin resistance, and brachial artery vasodilator function in Framingham Offspring participants without clinical evidence of cardiovascular disease. Am J Cardiol 2008;101:82–8.10.1016/j.amjcard.2007.07.053Search in Google Scholar PubMed PubMed Central

72. Huang AL, Silver AE, Shvenke E, Schopfer DW, Jahangir E, Titas MA, Shpilman A, Menzoian JO, Watkins MT, Raffetto JD, Gibbons G, Woodson J, Shaw PM, Dhadly M, Eberhardt RT, Keaney JF, Jr., Gokce N, Vita JA. Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol 2007;27:2113–9.10.1161/ATVBAHA.107.147322Search in Google Scholar PubMed PubMed Central

73. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation 2009;120:502–9.10.1161/CIRCULATIONAHA.109.864801Search in Google Scholar PubMed PubMed Central

74. Arkin JM, Alsdorf R, Bigornia S, Palmisano J, Beal R, Istfan N, Hess D, Apovian CM, Gokce N. Relation of cumulative weight burden to vascular endothelial dysfunction in obesity. Am J Cardiol 2008;101:98–101.10.1016/j.amjcard.2007.07.055Search in Google Scholar PubMed PubMed Central

75. Woo KS, Chook P, Yu CW, Sung RY, Qiao M, Leung SS, Lam CW, Metreweli C, Celermajer DS. Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening. Int J Obes Relat Metab Disord 2004;28:852–7.10.1038/sj.ijo.0802539Search in Google Scholar PubMed

76. Perticone F, Ceravolo R, Candigliota M, Ventura G, Iacopino S, Sinopoli F, Mattioli PL. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes 2001;50:159–65.10.2337/diabetes.50.1.159Search in Google Scholar PubMed

77. Parikh NI, Keyes MJ, Larson MG, Pou KM, Hamburg NM, Vita JA, O’Donnell CJ, Vasan RS, Mitchell GF, Hoffmann U, Fox CS, Benjamin EJ. Visceral and subcutaneous adiposity and brachial artery vasodilator function. Obesity (Silver Spring) 2009;17:2054–9.10.1038/oby.2009.60Search in Google Scholar PubMed PubMed Central

78. Hashimoto M, Akishita M, Eto M, Kozaki K, Ako J, Sugimoto N, Yoshizumi M, Toba K, Ouchi Y. The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation. Int J Obes Relat Metab Disord 1998;22:477–84.10.1038/sj.ijo.0800620Search in Google Scholar PubMed

79. Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, Stumvoll M, Bluher M. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010;299:E506–15.10.1152/ajpendo.00586.2009Search in Google Scholar PubMed

80. Rosenquist KJ, Pedley A, Massaro JM, Therkelsen KE, Murabito JM, Hoffmann U, Fox CS. Visceral and subcutaneous fat quality and cardiometabolic risk. JACC Cardiovasc Imaging 2013;6:762–71.10.1016/j.jcmg.2012.11.021Search in Google Scholar PubMed PubMed Central

81. Rosenquist KJ, Massaro JM, Pedley A, Long MT, Kreger BE, Vasan RS, Murabito JM, Hoffmann U, Fox CS. Fat quality and incident cardiovascular disease, all-cause mortality, and cancer mortality. J Clin Endocrinol Metab 2015;100:227–34.10.1210/jc.2013-4296Search in Google Scholar PubMed PubMed Central

82. Grizelj I, Cavka A, Bian JT, Szczurek M, Robinson A, Shinde S, Nguyen V, Braunschweig C, Wang E, Drenjancevic I, Phillips SA. Reduced flow-and acetylcholine-induced dilations in visceral compared to subcutaneous adipose arterioles in human morbid obesity. Microcirculation 2015;22:44–53.10.1111/micc.12164Search in Google Scholar PubMed PubMed Central

83. Virdis A, Santini F, Colucci R, Duranti E, Salvetti G, Rugani I, Segnani C, Anselmino M, Bernardini N, Blandizzi C, Salvetti A, Pinchera A, Taddei S. Vascular generation of tumor necrosis factor-alpha reduces nitric oxide availability in small arteries from visceral fat of obese patients. J Am Coll Cardiol 2011;58:238–47.10.1016/j.jacc.2011.01.050Search in Google Scholar PubMed

84. Virdis A, Duranti E, Rossi C, Dell’agnello U, Santini E, Anselmino M, Chiarugi M, Taddei S, Solini A. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue. Eur Heart J 2014; Epub ahead of print.10.1093/eurheartj/ehu072Search in Google Scholar PubMed

85. Dharmashankar K, Welsh A, Wang J, Kizhakekuttu TJ, Ying R, Gutterman DD, Widlansky ME. Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function. Am J Hypertens 2012;25:528–34.10.1038/ajh.2012.8Search in Google Scholar PubMed PubMed Central

86. Freed JK, Beyer AM, LoGiudice JA, Hockenberry JC, Gutterman DD. Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circ Res 2014;115:525–32.10.1161/CIRCRESAHA.115.303881Search in Google Scholar PubMed PubMed Central

87. Kizhakekuttu TJ, Wang J, Dharmashankar K, Ying R, Gutterman DD, Vita JA, Widlansky ME. Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 2012;32:2531–9.10.1161/ATVBAHA.112.256024Search in Google Scholar PubMed PubMed Central

88. Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, Jeziorska M, Laing I, Yates AP, Pemberton PW, Malik RA, Heagerty AM. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 2009;119:1661–70.10.1161/CIRCULATIONAHA.108.821181Search in Google Scholar PubMed

89. Grassi G, Seravalle G, Scopelliti F, Dell’Oro R, Fattori L, Quarti-Trevano F, Brambilla G, Schiffrin EL, Mancia G. Structural and functional alterations of subcutaneous small resistance arteries in severe human obesity. Obesity (Silver Spring) 2010;18:92–8.10.1038/oby.2009.195Search in Google Scholar PubMed

90. Ohman MK, Shen Y, Obimba CI, Wright AP, Warnock M, Lawrence DA, Eitzman DT. Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008;117:798–805.10.1161/CIRCULATIONAHA.107.717595Search in Google Scholar PubMed PubMed Central

91. Kearney MT, Duncan ER, Kahn M, Wheatcroft SB. Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Exp Physiol 2008;93:158–63.10.1113/expphysiol.2007.039172Search in Google Scholar PubMed

92. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev 2007;28:463–91.10.1210/er.2007-0006Search in Google Scholar PubMed

93. Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2012;32:2052–9.10.1161/ATVBAHA.111.241919Search in Google Scholar PubMed PubMed Central

94. Tabit CE, Shenouda SM, Holbrook M, Fetterman JL, Kiani S, Frame AA, Kluge MA, Held A, Dohadwala MM, Gokce N, Farb MG, Rosenzweig J, Ruderman N, Vita JA, Hamburg NM. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation 2013;127:86–95.10.1161/CIRCULATIONAHA.112.127514Search in Google Scholar PubMed PubMed Central

95. Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002;105:576–82.10.1161/hc0502.103333Search in Google Scholar PubMed

96. Duncan ER, Crossey PA, Walker S, Anilkumar N, Poston L, Douglas G, Ezzat VA, Wheatcroft SB, Shah AM, Kearney MT. Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes 2008;57:3307–14.10.2337/db07-1111Search in Google Scholar PubMed PubMed Central

97. Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000;101:676–81.10.1161/01.CIR.101.6.676Search in Google Scholar

98. Okon EB, Chung AW, Rauniyar P, Padilla E, Tejerina T, McManus BM, Luo H, van BC. Compromised arterial function in human type 2 diabetic patients. Diabetes 2005;54:2415–23.10.2337/diabetes.54.8.2415Search in Google Scholar PubMed

99. Fulton DJ. Mechanisms of vascular insulin resistance: a substitute Akt? Circ Res 2009;104:1035–7.10.1161/CIRCRESAHA.109.198028Search in Google Scholar PubMed PubMed Central

100. Sjostrom L, Peltonen M, Jacobson P, Sjostrom CD, Karason K, Wedel H, Ahlin S, Anveden A, Bengtsson C, Bergmark G, Bouchard C, Carlsson B, Dahlgren S, Karlsson J, Lindroos AK, Lonroth H, Narbro K, Naslund I, Olbers T, Svensson PA, Carlsson LM. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56–65.10.1001/jama.2011.1914Search in Google Scholar PubMed

101. Bigornia SJ, Farb MG, Tiwari S, Karki S, Hamburg NM, Vita JA, Hess DT, Lavalley MP, Apovian CM, Gokce N. Insulin status and vascular responses to weight loss in obesity. J Am Coll Cardiol 2013;62:2297–305.10.1016/j.jacc.2013.07.078Search in Google Scholar

102. Rojas-Rodriguez R, Gealekman O, Kruse ME, Rosenthal B, Rao K, Min S, Bellve KD, Lifshitz LM, Corvera S. Adipose tissue angiogenesis assay. Methods Enzymol 2014;537:75–91.10.1016/B978-0-12-411619-1.00005-7Search in Google Scholar

103. Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov 2010;9:107–15.10.1038/nrd3055Search in Google Scholar

104. Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP, Konings E, Jocken JW, Cajlakovic M, Ribitsch V, Clement K, Blaak EE. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 2011;124:67–76.10.1161/CIRCULATIONAHA.111.027813Search in Google Scholar

105. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 2009;58:718–25.10.2337/db08-1098Search in Google Scholar

106. Pasarica M, Rood J, Ravussin E, Schwarz JM, Smith SR, Redman LM. Reduced oxygenation in human obese adipose tissue is associated with impaired insulin suppression of lipolysis. J Clin Endocrinol Metab 2010;95:4052–5.10.1210/jc.2009-2377Search in Google Scholar

107. Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 2008;100:227–35.10.1017/S0007114508971282Search in Google Scholar

108. Gealekman O, Burkart A, Chouinard M, Nicoloro SM, Straubhaar J, Corvera S. Enhanced angiogenesis in obesity and in response to PPARgamma activators through adipocyte VEGF and ANGPTL4 production. Am J Physiol Endocrinol Metab 2008;295:E1056–64.10.1152/ajpendo.90345.2008Search in Google Scholar

109. Sung HK, Doh KO, Son JE, Park JG, Bae Y, Choi S, Nelson SM, Cowling R, Nagy K, Michael IP, Koh GY, Adamson SL, Pawson T, Nagy A. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab 2013;17:61–72.10.1016/j.cmet.2012.12.010Search in Google Scholar

110. Elias I, Franckhauser S, Ferre T, Vila L, Tafuro S, Munoz S, Roca C, Ramos D, Pujol A, Riu E, Ruberte J, Bosch F. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes 2012;61:1801–13.10.2337/db11-0832Search in Google Scholar

111. Ngo DT, Farb MG, Kikuchi R, Karki S, Tiwari S, Bigornia SJ, Bates DO, Lavalley MP, Hamburg NM, Vita JA, Hess DT, Walsh K, Gokce N. Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation 2014;130:1072–80.10.1161/CIRCULATIONAHA.113.008171Search in Google Scholar PubMed PubMed Central

112. Villaret A, Galitzky J, Decaunes P, Esteve D, Marques MA, Sengenes C, Chiotasso P, Tchkonia T, Lafontan M, Kirkland JL, Bouloumie A. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 2010;59:2755–63.10.2337/db10-0398Search in Google Scholar PubMed PubMed Central

113. Zhang QX, Magovern CJ, Mack CA, Budenbender KT, Ko W, Rosengart TK. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis. J Surg Res 1997;67:147–54.10.1006/jsre.1996.4983Search in Google Scholar PubMed

114. Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K. An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med 2014;20:1464–71.10.1038/nm.3703Search in Google Scholar PubMed PubMed Central

115. Ashrafian H, le Roux CW, Darzi A, Athanasiou T. Effects of bariatric surgery on cardiovascular function. Circulation 2008;118:2091–102.10.1161/CIRCULATIONAHA.107.721027Search in Google Scholar PubMed

116. Bigornia SJ, Mott MM, Hess DT, Apovian CM, McDonnell ME, Duess MA, Kluge MA, Fiscale AJ, Vita JA, Gokce N. Long-term successful weight loss improves vascular endothelial function in severely obese individuals. Obesity (Silver Spring) 2010;18:754–9.10.1038/oby.2009.482Search in Google Scholar PubMed PubMed Central

117. Gokce N, Vita JA, McDonnell M, Forse AR, Istfan N, Stoeckl M, Lipinska I, Keaney JF, Jr., Apovian CM. Effect of medical and surgical weight loss on endothelial vasomotor function in obese patients. Am J Cardiol 2005;95:266–8.10.1016/j.amjcard.2004.09.016Search in Google Scholar PubMed

118. Owan T, Avelar E, Morley K, Jiji R, Hall N, Krezowski J, Gallagher J, Williams Z, Preece K, Gundersen N, Strong MB, Pendleton RC, Segerson N, Cloward TV, Walker JM, Farney RJ, Gress RE, Adams TD, Hunt SC, Litwin SE. Favorable changes in cardiac geometry and function following gastric bypass surgery: 2-year follow-up in the Utah obesity study. J Am Coll Cardiol 2011;57:732–9.10.1016/j.jacc.2010.10.017Search in Google Scholar PubMed PubMed Central

119. Raitakari M, Ilvonen T, Ahotupa M, Lehtimaki T, Harmoinen A, Suominen P, Elo J, Hartiala J, Raitakari OT. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol 2004;24:124–8.10.1161/01.ATV.0000109749.11042.7cSearch in Google Scholar PubMed

120. Sciacqua A, Candigliota M, Ceravolo R, Scozzafava A, Sinopoli F, Corsonello A, Sesti G, Perticone F. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity. Diabetes Care 2003;26:1673–8.10.2337/diacare.26.6.1673Search in Google Scholar PubMed

121. Romeo S, Maglio C, Burza MA, Pirazzi C, Sjoholm K, Jacobson P, Svensson PA, Peltonen M, Sjostrom L, Carlsson LM. Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes. Diabetes Care 2012;35:2613–7.10.2337/dc12-0193Search in Google Scholar PubMed PubMed Central

122. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, Lindroos AK, Lonroth H, Naslund I, Olbers T, Stenlof K, Torgerson J, Agren G, Carlsson LM. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741–52.10.1056/NEJMoa066254Search in Google Scholar PubMed

123. Gaborit B, Jacquier A, Kober F, Abdesselam I, Cuisset T, Boullu-Ciocca S, Emungania O, Alessi MC, Clement K, Bernard M, Dutour A. Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J Am Coll Cardiol 2012;60:1381–9.10.1016/j.jacc.2012.06.016Search in Google Scholar PubMed

124. van Schinkel LD, Sleddering MA, Lips MA, Jonker JT, de RA, Lamb HJ, Jazet IM, Pijl H, Smit JW. Effects of bariatric surgery on pericardial ectopic fat depositions and cardiovascular function. Clin Endocrinol (Oxf) 2014;81:689–95.10.1111/cen.12402Search in Google Scholar PubMed

125. Snel M, Jonker JT, Hammer S, Kerpershoek G, Lamb HJ, Meinders AE, Pijl H, de RA, Romijn JA, Smit JW, Jazet IM. Long-term beneficial effect of a 16-week very low calorie diet on pericardial fat in obese type 2 diabetes mellitus patients. Obesity (Silver Spring) 2012;20:1572–6.10.1038/oby.2011.390Search in Google Scholar PubMed

126. Shah RV, Murthy VL, Abbasi SA, Blankstein R, Kwong RY, Goldfine AB, Jerosch-Herold M, Lima JA, Ding J, Allison MA. Visceral adiposity and the risk of metabolic syndrome across body mass index: The MESA Study. JACC Cardiovasc Imaging 2014;7:1221–35.10.1016/j.jcmg.2014.07.017Search in Google Scholar PubMed PubMed Central

127. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005;54:2277–86.10.2337/diabetes.54.8.2277Search in Google Scholar PubMed

128. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Stich V, Cancello R, Langin D. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 2004;18:1657–69.10.1096/fj.04-2204comSearch in Google Scholar PubMed

129. De CC, Porteri E, Rizzoni D, Corbellini C, La BE, Boari GE, Pilu A, Mittempergher F, Di BE, Casella C, Nascimbeni R, Rosei CA, Ruggeri G, Caimi L, Rosei EA. Effects of weight loss on structural and functional alterations of subcutaneous small arteries in obese patients. Hypertension 2011;58:29–36.10.1161/HYPERTENSIONAHA.111.171082Search in Google Scholar PubMed

Received: 2014-12-23
Accepted: 2015-2-4
Published Online: 2015-3-6
Published in Print: 2015-2-1

©2015 by De Gruyter

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