Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms linking obesity with cardiovascular disease

Abstract

Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance — the core feature of type 2 diabetes — as well as alterations in lipids, blood pressure, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Schematic representation of how smoking might add to several mechanisms linking obesity to cardiovascular disease.
Figure 2: Disturbances in haemostasis and fibrinolysis as additional cardiovascular risk factors in relation to metabolic syndrome.
Figure 3: Both abdominal (visceral) fat and insulin resistance may contribute to cardiovascular disease in obesity.

References

  1. 1

    James, P. T., Rigby, N. & Leach, R. International Obesity Task Force. The obesity epidemic, metabolic syndrome and future prevention strategies. Eur. J. Cardiovasc. Prev. Rehabil. 11, 3–8 (2004).

    Article  PubMed  Google Scholar 

  2. 2

    Adams, K. F. et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N. Engl. J. Med. 355, 763–778 (2006).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Lakka, T. A., Lakka, H. M., Salonen, R., Kaplan, G. A. & Salonen, J. T. Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men. Atherosclerosis 154, 497–504 (2001).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Kenchaiah, S. et al. Obesity and the risk of heart failure. N. Engl. J. Med. 347, 305–313 (2002).

    Article  PubMed  Google Scholar 

  5. 5

    Hu, F. B. et al. Adiposity as compared with physical activity in predicting mortality among women. N. Engl. J. Med. 351, 2694–2703 (2004).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Berenson, G. S. et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N. Engl. J. Med. 338, 1650–1656 (1998).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Olshansky, S. J. et al. A potential decline in life expectancy in the United States in the 21st century. N. Engl. J. Med. 352, 1138–1145 (2005).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Eckel, R. H., Kahn, R., Robertson, R. M. & Rizza, R. A. Preventing cardiovascular disease and diabetes. A call to action from the American Diabetes Association and the American Heart Association. Circulation 113, 2943–2946 (2006).

    Article  PubMed  Google Scholar 

  9. 9

    Lau, D. C. W., Dhillon, B., Yan, H., Szmitko, P. E. & Verma, S. Adipokines: molecular links between obesity and atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 288, H2031–H2041 (2005).

  10. 10

    Poirier, P. et al. American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113, 898–918 (2006).

    Article  PubMed  Google Scholar 

  11. 11

    Peeters, A. et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann. Intern. Med. 138, 24–32 (2003).

    Article  PubMed  Google Scholar 

  12. 12

    Stevens, J., Cai, J., Evenson, K. R. & Thomas, R. Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study. Am. J. Epidemiol. 156, 832–841 (2002).

    Article  PubMed  Google Scholar 

  13. 13

    Pontiroli, A. E. et al. Body weight and glucose metabolism have a different effect on circulating levels of ICAM-1, E-selectin, and endothelin-1 in humans. Eur. J. Endocrinol. 150, 195–200 (2004).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Blann, A. D., Steele, C. & McCollum, C. N. The influence of smoking on soluble adhesion molecules and endothelial cell markers. Thromb. Res. 85, 433–438 (1997).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Iwashima, Y. et al. Association of hypoadiponectinemia with smoking habit in men. Hypertension 45, 1094–1100 (2005).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Matsuzawa, Y. The metabolic syndrome and adipocytokines. FEBS Lett. 580, 2917–2921 (2006).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Liu, R., Mizuta, M. & Matsukura, S. The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J. Pharmacol. Exp. Ther. 310, 52–58 (2004).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Facchini, F. S., Hollenbeck, C. B., Jeppesen, J., Chen, Y. D. & Reaven, G. M. Insulin resistance and cigarette smoking. Lancet 339, 1128–1130 (1992).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    van der Vaart, H., Postma, D. S., Timens, W. & Ten Hacken, N. H. T. Acute effects of cigarette smoking on inflammation and oxidative stress: a review. Thorax 59, 713–721 (2004).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Howard, B. V., Ruotolo, G. & Robbins, D. C. Obesity and dyslipidemia. Endocrinol. Metab. Clin. N. Am. 32, 855–867 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Yusuf, S. et al. INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364, 937–952 (2004).

    Article  PubMed  Google Scholar 

  22. 22

    Gaudet, D. et al. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 97, 871–877 (1998).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Nicholls, S. J. et al. Effects of obesity on lipid-lowering, anti-inflammatory and antiatherosclerotic benefits of atorvastatin or pravastatin in patients with coronary artery disease (from the REVERSAL study). Am. J. Cardiol. 97, 1553–1557 (2006).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Kwiterovich, P.O. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. Am. J. Cardiol. 90, 30i–47i (2002).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Taskinen, M.R. Lipoprotein lipase in diabetes. Diabetes Metab. Rev. 3, 551–570 (1987).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Howard, B. V. et al. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler. Thromb. Vasc. Biol. 20, 830–835 (2000).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Chan, D. C., Watts, G. F., Redgrave, T. G., Mori, T. A. Barrett, P. H. R. Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration. Metabolism 51, 1041–1046 (2002).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Frenais, R. et al. In vivo evidence for the role of lipoprotein lipase activity in the regulation of apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus. J. Clin. Endocrinol. Metab. 86, 1962–1967 (2001).

    CAS  PubMed  Google Scholar 

  29. 29

    Mertens, I. & Van Gaal, L. F. New International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment panel III (NCEP-ATPIII) criteria and the involvement of hemostasis and fibrinolysis in the metabolic syndrome. J. Thromb. Haemost. 4, 1164–1166 (2006).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Blair, S. N. & Church, T. S. The fitness, obesity, and health equation: is physical activity the common denominator? J. Am. Med. Assoc. 292, 1232–1234 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Li, T. Y. et al. Obesity as compared with physical activity in predicting risk of coronary heart disease in women. Circulation 113, 499–506 (2006).

    Article  PubMed  Google Scholar 

  32. 32

    Manson, J. E. et al. Body weight and mortality among women. N. Engl. J. Med. 333, 677–685 (1995).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Sandvik, L. et al. Physical fitness as a predictor of mortality among healthy, middle-aged Norwegian men. N. Engl. J. Med. 328, 533–537 (1993).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Nigro, J., Osman, N., Dart, A. M. & Little, P. J. Insulin resistance and atherosclerosis. Endocr. Rev. 27, 242–259 (2006).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Ferrannini, E. & Iozzo, P. Is insulin resistance atherogenic? A review of the evidence. Atheroscler. Suppl. 7, 5–10 (2006).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Smith, S. R. & Wilson, P. W. Free fatty acids and atherosclerosis — guilty or innocent? J. Clin. Endocrinol. Metab. 91, 2506–2508 (2006).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Pilz, S. et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J. Clin. Endocrinol. Metab. 91, 2542–2547 (2006).

    Article  Google Scholar 

  38. 38

    Graham, T. E. et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N. Engl. J. Med. 354, 2552–2563 (2006).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Abel, E. D. et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733 (2001).

    ADS  CAS  Article  Google Scholar 

  40. 40

    Summers, S. A. et al. Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res. 45, 42–72 (2006).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Rexrode, K. M. et al. Abdominal adiposity and coronary heart disease in women. J. Am. Med. Assoc. 280, 1843–1848 (1998).

    Article  Google Scholar 

  42. 42

    Després, J. P., Lemieux, I. & Prud'homme, D. Treatment of obesity: need to focus on high risk abdominally obese patients. Br. Med. J. 322, 716–720 (2001).

    Article  Google Scholar 

  43. 43

    Kuk, J. L. et al. Visceral fat is an independent predictor of all-cause mortality in men. Obesity 14, 336–342 (2006).

    Article  PubMed  Google Scholar 

  44. 44

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Cancello, R. & Clement, K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG 113, 1141–1147 (2006).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Bornstein, S. R. et al. Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes 49, 532–538 (2000).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Björntorp, P. 'Portal' adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 10, 493–496 (1990).

    Article  PubMed  Google Scholar 

  48. 48

    Yki-Jarvinen, H. & Westerbacka, J. The fatty liver and insulin resistance. Curr. Mol. Med. 5, 287–295 (2005).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Yusuf, S. et al. INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 366, 1640–1649 (2005).

    Article  PubMed  Google Scholar 

  50. 50

    Montani, J. -P. et al. Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases. Int. J. Obesity 28, S58–S65 (2004).

    CAS  Article  Google Scholar 

  51. 51

    Zhou, Y. T. et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc. Natl Acad. Sci. USA 97, 1784–1789 (2000).

    ADS  CAS  Article  PubMed  Google Scholar 

  52. 52

    McGavock, J. M., Victor, R. G., Unger, R. H. & Szczepaniak, L. S. American College of Physicians and the American Physiological Society. Adiposity of the heart, revisited. Ann. Intern. Med. 144, 517–524 (2006).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Szczepaniak, L. S. et al. Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn. Reson. Med. 49, 417–423 (2003).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Verlohren, S. et al. Visceral periadventitial adipose tissue regulates arterial tone of mesenteric arteries. Hypertension 44, 271–276 (2004).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Arita, Y. et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105, 2893–2898 (2002).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Konstantinides, S., Schafer, K., Koschnick, S. & Loskutoff, D. J. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J. Clin. Invest. 108, 1533–1540 (2001).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Singhal, A. et al. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 106, 1919–1924 (2002).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Mertens, I., Considine, R. V., Van der Planken, M. & Van Gaal, L. F. Hemostasis and fibrinolysis in non-diabetic overweight and obese men and women. Is there still a role for leptin? Eur. J. Endocrinol. 155, 477–484 (2006).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Kumada, M. et al. Adiponectin specifically increases tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109, 2046–2049 (2004).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Kobayashi, H. et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ. Res. 94, e27–e31 (2004).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Ouchi, N. et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42, 231–232 (2003).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Fukuhara, A. et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426–430 (2005).

    ADS  CAS  Article  PubMed  Google Scholar 

  63. 63

    Haider, D. G. et al. The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia 49, 1909–1914 (2006).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Mertens, I. & Van Gaal, L. F. Obesity, haemostasis and the fibrinolytic system. Obes. Rev. 3, 85–101 (2002).

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Bastelica, D. et al. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits. Arterioscler. Thromb. Vasc. Biol. 22, 173–178 (2002).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Alessi, M. C. et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler. Thromb. Vasc. Biol. 23, 1262–1268 (2003).

    Article  Google Scholar 

  67. 67

    Alessi, M. C. & Juhan-Vague, I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler. Thromb. Vasc. Biol. 26, 200–207 (2006).

    Article  Google Scholar 

  68. 68

    Esmon, C. T. The interactions between inflammation and coagulation. Br. J. Haematol. 131, 417–430 (2005).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Hanley, A. J. et al. Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity. Diabetes 53, 1773–1781 (2004).

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Devaraj, S., Xu, D. Y. & Jialal, I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 107, 398–404 (2003).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Ceriello, A. & Motz, E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol. 24, 816–823 (2004).

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Holvoet, P. et al. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging and body composition cohort. Diabetes 53, 1068–1073 (2004).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Maddux, B. A. et al. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of alpha-lipoic acid. Diabetes 50, 404–410 (2001).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Esposito, K. et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106, 2067–2072 (2002).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Tripathy, D. et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52, 2882–2887 (2003).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Sattar, N. et al. Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes 53, 2855–2860 (2004).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Libby, P., Ridker, P. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Berg, A. H., Scherer, P. E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 96, 939–949 (2005).

    CAS  Article  PubMed  Google Scholar 

  79. 79

    Berg, A. H., Lin, Y., Lisanti, M. P. & Scherer, P. E. Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. Am. J. Physiol. Endocrinol. Metab. 287, E1178–E1188 (2004).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Rutter, M. K. et al. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation 107, 448–454 (2003).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Young, M. E. et al. Adaptation and maladaptation of the heart in diabetes: part II: potential mechanisms. Circulation 105, 1861–1870 (2002).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank A. Verrijken and P.-J. Van Gaal from the Metabolic Unit for their help with literature searches.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Van Gaal, L., Mertens, I. & De Block, C. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006). https://doi.org/10.1038/nature05487

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing