Skip to main content

Cytokine Abnormalities in the Etiology of the Cardiometabolic Syndrome

Abstract

The cardiometabolic syndrome comprises a cluster of risk factors, including abdominal obesity, dyslipidemia, hypertension, insulin resistance/glucose intolerance, and proteinuria. This syndrome is due, in part, to the accumulation of visceral fat, which promotes synthesis of proinflammatory adipokines resulting in a visceral adipose tissue-specific increase in reactive oxygen species derived from NADPH oxidase. Adipose tissue oxidative stress results in the development of systemic oxidative stress and inflammation, which further lead to development of metabolic dyslipidemia, impaired glucose metabolism, renal disease, and hypertension. Importantly, visceral—not subcutaneous—fat is the significant source of the circulating adipokines that promote these systemic abnormalities. Chronic low-grade inflammation develops within adipose tissue because of the additional infiltration and accumulation of inflammatory macrophages. There is evidence that lifestyle changes, bariatric surgery, and/or administration of insulin-sensitizing, anti-inflammatory, or antihypertensive drugs that address the risk factors promoting the cardiometabolic syndrome act, in part, by promoting an anti-inflammatory adipokine profile in visceral fat.

This is a preview of subscription content, access via your institution.

References

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

  1. Whaley-Connell A, Sowers JR: Hypertension and insulin resistance. Hypertension 2009, 54(3):462–464.

    Article  CAS  PubMed  Google Scholar 

  2. • Sowers JR: Metabolic risk factors and renal disease. Kidney Int 2007, 71(8):719–720. This is a recent editorial on the interactions of various metabolic risk factors, hypertension, insulin resistance, inflammation, and oxidative stress. It reviews the potential mechanisms by which obesity and other metabolic risk factors promote kidney disease.

    Article  CAS  PubMed  Google Scholar 

  3. • Kurukulasuriya LR, Stas S, Lastra G, et al.: Hypertension in obesity. Endocrinol Metab Clin North Am 2008, 37(3):647–662. This article reviews the impact of obesity on inflammation and oxidative stress.

    Article  CAS  PubMed  Google Scholar 

  4. •• Whaley-Connell A, Sowers JR: Obesity, insulin resistance, and nocturnal systolic blood pressure. Hypertension 2008, 51(3):620–621. This article reviews the impact of obesity on inflammation and oxidative stress.

    Article  CAS  PubMed  Google Scholar 

  5. Govindarajan G, Whaley-Connell A, Mugo M, et al.: The cardiometabolic syndrome as a cardiovascular risk factor. Am J Med Sci 2005, 330:311–318.

    Article  PubMed  Google Scholar 

  6. Alberti KG, Eckel RH, Grundy SM, et al.: Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120:1640–1645.

    Article  CAS  PubMed  Google Scholar 

  7. Wei Y, Chen K, Whaley-Connell AT, et al.: Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species. Am J Physiol Regul Integr Comp Physiol 2008, 294(3):R673–R680.

    CAS  PubMed  Google Scholar 

  8. • Sowers JR: Endocrine functions of adipose tissue; focus on adiponectin. Clin Cornerstone 2008, 9(1):32–38. This is a review of the cytokines produced by adipose tissue.

    Article  PubMed  Google Scholar 

  9. Cnop M, Havel PJ, Utzschneider KM, et al.: Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 2003, 46:459–469.

    CAS  PubMed  Google Scholar 

  10. Cano P, Cardinali DP, Rios-Lugo MJ, et al.: Effect of a high-fat diet on 24-hour pattern of circulating adipocytokines in rats. Obesity (Silver Spring) 2009, 17:1866–1871.

    Article  CAS  Google Scholar 

  11. Berg AH, Combs TP, Du X, et al.: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001, 7:947–953.

    Article  CAS  PubMed  Google Scholar 

  12. Fruebis J, Tsao TS, Javorschi S, et al.: Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001, 98:2005–2010.

    Article  CAS  PubMed  Google Scholar 

  13. Matsubara M, Maruoka S, Katayose S: Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 2002, 147:173–180.

    Article  CAS  PubMed  Google Scholar 

  14. Arita Y, Kihara S, Ouchi N, et al.: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999, 257:79–83.

    Article  CAS  PubMed  Google Scholar 

  15. Yamauchi T, Kamon J, Waki H, et al.: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001, 7:941–946.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS: Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997, 389:610–614.

    Article  CAS  PubMed  Google Scholar 

  18. Kubota N, Terauchi Y, Yamauchi T, et al.: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002, 277:25863–25866.

    Article  CAS  PubMed  Google Scholar 

  19. Hara K, Boutin P, Mori Y, et al.: Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002, 51:536–540.

    Article  CAS  PubMed  Google Scholar 

  20. Kondo H, Shimomura I, Matsukawa Y, et al.: Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 2002, 51:2325–2328.

    Article  CAS  PubMed  Google Scholar 

  21. Li S, Shin HJ, Ding EL, van Dam RM: Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2009, 302:179–188.

    Article  CAS  PubMed  Google Scholar 

  22. Furukawa S, Fujita T, Shimabukuro M, et al.: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004, 114:1752–1761.

    CAS  PubMed  Google Scholar 

  23. Gaster M, Staehr P, Beck-Nielsen H, et al.: GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: Is insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes 2001, 50:1324–1329.

    Article  CAS  PubMed  Google Scholar 

  24. Daugaard JR, Richter EA: Relationship between muscle fibre composition, glucose transporter protein 4 and exercise training: possible consequences in non-insulin-dependent diabetes mellitus. Acta Physiol Scand 2001, 171:267–276.

    Article  CAS  PubMed  Google Scholar 

  25. Wei Y, Sowers JR, Nistala R, et al.: Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem 2006, 281:35137–35146.

    Article  CAS  PubMed  Google Scholar 

  26. Kamei N, Tobe K, Suzuki R, et al.: Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006, 281:26602–26614.

    Article  CAS  PubMed  Google Scholar 

  27. Xu H, Barnes GT, Yang Q, et al.: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112:1821–1830.

    CAS  PubMed  Google Scholar 

  28. Weisberg SP, McCann D, Desai M, et al.: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112:1796–1808.

    CAS  PubMed  Google Scholar 

  29. Lumeng CN, Bodzin JL, Saltiel AR: Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007, 117:175–184.

    Article  CAS  PubMed  Google Scholar 

  30. Cancello R, Tordjman J, Poitou C, et al.: Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 2006, 55:1554–1561.

    Article  CAS  PubMed  Google Scholar 

  31. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 2005, 25:2062–2068.

    Article  CAS  PubMed  Google Scholar 

  32. • Feuerer M, Herrero L, Cipolletta D, et al.: Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009, 15:930–939. This article reviews the role of fat in T-cell-mediated immunity.

    Article  CAS  PubMed  Google Scholar 

  33. Greenstein AS, Khavandi K, Withers SB, et al.: Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 2009, 119:1661–1670.

    Article  CAS  PubMed  Google Scholar 

  34. Grill HJ, Kaplan JM: The neuroanatomical axis for control of energy balance. Front Neuroendocrinol 2002, 23:2–40.

    Article  CAS  PubMed  Google Scholar 

  35. Shi P, Raizada MK, Sumners C: Brain cytokines as neuromodulators in cardiovascular control. Clin Exp Pharmacol Physiol 2010, 37(2):e52–57.

    Article  CAS  PubMed  Google Scholar 

  36. Hausberg M, Morgan DA, Chapleau MA, et al.: Differential modulation of leptin-induced sympathoexcitation by baroreflex activation. J Hypertens 2002, 20:1633–1641.

    Article  CAS  PubMed  Google Scholar 

  37. Guzik TJ, Marvar PJ, Czesnikiewicz-Guzik M, Korbut R: Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction. J Physiol Pharmacol 2007, 58:591–610.

    CAS  PubMed  Google Scholar 

  38. Psilopanagioti A, Papadaki H, Kranioti EF, et al.: Expression of adiponectin and adiponectin receptors in human pituitary gland and brain. Neuroendocrinology 2009, 89:38–47.

    Article  CAS  PubMed  Google Scholar 

  39. Ahima RS, Lazar MA: Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 2008, 22:1023–1031.

    Article  CAS  PubMed  Google Scholar 

  40. Shimomura I, Hammer RE, Ikemoto S, et al.: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401:73–76.

    Article  CAS  PubMed  Google Scholar 

  41. Jensen DR, Schlaepfer IR, Morin CL, et al.: Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase. Am J Physiol 1997, 273:R683–R689.

    CAS  PubMed  Google Scholar 

  42. Stevens VJ, Obarzanek E, Cook NR, et al.: Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med 2001, 134:1–11.

    CAS  PubMed  Google Scholar 

  43. Ziccardi P, Nappo F, Giugliano G, et al.: Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002, 105:804–809.

    Article  CAS  PubMed  Google Scholar 

  44. Abate N, Garg A, Peshock RM, et al.: Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest 1995, 96:88–98.

    Article  CAS  PubMed  Google Scholar 

  45. Bobbert T, Rochlitz H, Wegewitz U, et al.: Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 2005, 54:2712–2719.

    Article  CAS  PubMed  Google Scholar 

  46. Yang WS, Lee WJ, Funahashi T, et al.: Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001, 86:3815–3819.

    Article  CAS  PubMed  Google Scholar 

  47. Goldfine AB, Shoelson SE, Aguirre V: Expansion and contraction: treating diabetes with bariatric surgery. Nat Med 2009, 15:616–617.

    Article  CAS  PubMed  Google Scholar 

  48. Buchwald H, Estok R, Fahrbach K, et al.: Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009, 122:248–256.

    Article  PubMed  Google Scholar 

  49. Moschen AR, Molnar C, Wolf AM, et al.: Effects of weight loss induced by bariatric surgery on hepatic adipocytokine expression. J Hepatol 2009, 51:765–777.

    Article  CAS  PubMed  Google Scholar 

  50. Araki K, Masaki T, Katsuragi I, et al.: Effects of pravastatin on obesity, diabetes, and adiponectin in diet-induced obese mice. Obesity (Silver Spring) 2008, 16:2068–2073.

    Article  CAS  Google Scholar 

  51. Combs TP, Wagner JA, Berger J, et al.: Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 2002, 143:998–1007.

    Article  CAS  PubMed  Google Scholar 

  52. Hansmann G, Wagner RA, Schellong S, et al.: Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation. Circulation 2007, 115(10):1275–1284.

    CAS  PubMed  Google Scholar 

  53. Mohapatra J, Sharma M, Singh S, et al.: Subtherapeutic dose of pioglitazone reduces expression of inflammatory adipokines in db/db mice. Pharmacology 2009, 84:203–210.

    Article  CAS  PubMed  Google Scholar 

  54. McCall KL, Craddock D, Edwards K: Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis. Pharmacotherapy 2006, 26:1297–1306.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James R. Sowers.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

DeMarco, V.G., Johnson, M.S., Whaley-Connell, A.T. et al. Cytokine Abnormalities in the Etiology of the Cardiometabolic Syndrome. Curr Hypertens Rep 12, 93–98 (2010). https://doi.org/10.1007/s11906-010-0095-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-010-0095-5

Keywords

  • Metabolic syndrome
  • CMS
  • Hypertension
  • Adipokines
  • Oxidative stress
  • Insulin resistance