Obesity, Inflammation, and Vascular Disease

The role of the adipose tissue as an endocrine organ
  • Paolo Calabro
  • Edward T. H. Yeh
Part of the Subcellular Biochemistry book series (SCBI, volume 42)

Insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of central fat. With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to influence several aspects in the pathogenesis of obesity-related diseases

Until relatively recently, the role of fat itself in the development of obesity and its consequences was considered to be a passive one; adipocytes were considered to be little more than storage cells for fat. It is now clear that, in addition to storing calories as triglycerides, they also secrete a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. This production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications

Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This remarkable understanding is allowing us to more clearly define the role that adipocytes play in health and in obesity and how inflammatory mediators act as signaling molecules in this process

Moreover, on a molecular level, we are beginning to comprehend how such variables as hormonal control, exercise, food intake, and genetic variation interact and result in a given phenotype, and how pharmacological intervention may modulate adipose tissue biology


Insulin Resistance Adipose Tissue Arterioscler Thromb Vasc Biol Human Adipose Tissue Resistin Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation 1998; 97:2099–2100.PubMedGoogle Scholar
  2. 2.
    Grundy SM. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation 2002; 105:2696–2698.PubMedGoogle Scholar
  3. Sowers JR. Obesity as a cardiovascular risk factor. Am J Med 2003; 115 Suppl 8A:37S–41S.PubMedGoogle Scholar
  4. 4.
    Sharma AM. Adipose tissue: a mediator of cardiovascular risk. IntJ Obes Relat Metab Disord 2002; 26 Suppl 4:S5–7.PubMedGoogle Scholar
  5. 5.
    Engeli S, Sharma AM. Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res 2000; 32:485–499.PubMedGoogle Scholar
  6. 6.
    Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004; 30:13–19.PubMedGoogle Scholar
  7. 7.
    Poirier P, Eckel RH. Obesity and cardiovascular disease. Curr Atheroscler Rep 2002; 4:448–453.PubMedGoogle Scholar
  8. 8.
    Peelman F, Waelput W, Iserentant H, Lavens D, Eyckerman S, Zabeau L, Tavernier J. Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases. Prog Lipid Res 2004; 43:283–301.PubMedGoogle Scholar
  9. 9.
    Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, HottaK, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules:adipocyte-derived plasma protein adiponectin. Circulation 1999; 100:2473–2476.PubMedGoogle Scholar
  10. 10.
    Shuldiner AR, Yang R, Gong DW. Resistin, obesity and insulin resistance–the emerging role of the adipocyte as an endocrine organ. N Engl J Med 2001; 345:1345–1346.PubMedGoogle Scholar
  11. 11.
    Bullo-Bonet M, Garcia-Lorda P, Lopez-Soriano FJ, Argiles JM, Salas-Salvado J. Tumour necrosis factor, a key role in obesity? FEBS Lett 1999; 451:215–219.PubMedGoogle Scholar
  12. 12.
    Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation,obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148:209–214.PubMedGoogle Scholar
  13. 13.
    Cinti S. The adipose organ: morphological perspectives of adipose tissues. Proc Nutr Soc 2001; 60:319–328.PubMedGoogle Scholar
  14. 14.
    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84:277–359.PubMedGoogle Scholar
  15. 15.
    Rennie KL, Jebb SA. Prevalence of obesity in Great Britain. Obes Rev 2005; 6:11–12.PubMedGoogle Scholar
  16. 16.
    Prentice AM, Jebb SA. Obesity in Britain: gluttony or sloth? Bmj1995; 311:437–439.PubMedGoogle Scholar
  17. 17.
    Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105:271–278.PubMedGoogle Scholar
  18. 18.
    Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptinreverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401:73–76.PubMedGoogle Scholar
  19. 19.
    Engstrom G, Stavenow L, Hedblad B, Lind P, Eriksson KF, Janzon L, Lindgarde F. Inflammation-sensitive plasma proteins, diabetes, andmortality and incidence of myocardial infarction and stroke: a population-based study. Diabetes 2003; 52:442–447.PubMedGoogle Scholar
  20. 20.
    Festa A, D’Agostino R Jr, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 2001; 25:1407–1415.PubMedGoogle Scholar
  21. 21.
    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive proteinin healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19:972–978.PubMedGoogle Scholar
  22. 22.
    Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 2003; 11:525–531.PubMedGoogle Scholar
  23. 23.
    Das UN. Is obesity an inflammatory condition? Nutrition 2001; 17:953–966.PubMedGoogle Scholar
  24. 24.
    Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 2003; 27 Suppl 3:S53–55.PubMedGoogle Scholar
  25. 25.
    Yudkin JS. Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obes Relat Metab Disord 2003; 27 Suppl 3:S25–28.PubMedGoogle Scholar
  26. 26.
    Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 2003; 108:1930–1932.PubMedGoogle Scholar
  27. 27.
    Calabro P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol 2005; 46:1112–1113.PubMedGoogle Scholar
  28. 28.
    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; 112:1796–1808.PubMedGoogle Scholar
  29. 29.
    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; 112:1821–1830.PubMedGoogle Scholar
  30. 30.
    Calabro P, Chang DW, Willerson JT, Yeh ET. Production of C-reactive protein and serum amyloid A in response to inflammatory cytokines by human adipocytes. Eur H Journal 2005; 26:334–335.Google Scholar
  31. 31.
    Cousin B, Munoz O, Andre M, Fontanilles AM, Dani C, Cousin JL, Laharrague P, Casteilla L, Penicaud L. A role for preadipocytes as macrophage-like cells. Faseb J 1999; 13:305–312.PubMedGoogle Scholar
  32. 32.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257:79–83.PubMedGoogle Scholar
  33. 33.
    Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20:1595–1599.PubMedGoogle Scholar
  34. 34.
    Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 2000; 102:1296–1301.PubMedGoogle Scholar
  35. 35.
    Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001; 175:81–92.PubMedGoogle Scholar
  36. 36.
    Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J. Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-alpha. Biochem Biophys Res Commun 1997; 235:94–98.PubMedGoogle Scholar
  37. 37.
    Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100:7265–7270.PubMedGoogle Scholar
  38. 38.
    Skurk T, Herder C, Kraft I, Muller-Scholze S, Hauner H, Kolb H. Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 2005; 146:1006–1011.PubMedGoogle Scholar
  39. 39.
    Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-alpha. Am J Physiol Endocrinol Metab 2005; 288:E731–740.PubMedGoogle Scholar
  40. 40.
    Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004; 92:347–355.PubMedGoogle Scholar
  41. 41.
    Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 2002; 51:2467–2473.PubMedGoogle Scholar
  42. 42.
    Hopfl G, Ogunshola O, Gassmann M. HIFs and tumors–causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004; 286:R608–623.PubMedGoogle Scholar
  43. 43.
    Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr OpinCell Biol 2001; 13:167–171.Google Scholar
  44. 44.
    Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. Faseb J 2002; 16:1151–1162.PubMedGoogle Scholar
  45. 45.
    Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M,Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord 2003; 27:1187–1195.PubMedGoogle Scholar
  46. 46.
    Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11:327–332.PubMedGoogle Scholar
  47. 47.
    Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 2:568–582.PubMedGoogle Scholar
  48. 48.
    Samad F, Yamamoto K, Pandey M, Loskutoff DJ. Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol Med 1997; 3:37–48.PubMedGoogle Scholar
  49. 49.
    Zhang B, Graziano MP, Doebber TW, Leibowitz MD, White-Carrington S, Szalkowski DM, Hey PJ, Wu M, Cullinan CA, Bailey P, Lollmann B, Frederich R, Flier JS, Strader CD, Smith RG. Down-regulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 1996; 271:9455–9459.PubMedGoogle Scholar
  50. 50.
    Eriksson P, Van Harmelen V, Hoffstedt J, Lundquist P, Vidal H, Stemme V, Hamsten A, Arner P, Reynisdottir S. Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 2000; 83:545–548.PubMedGoogle Scholar
  51. 51.
    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; 83:847–850.PubMedGoogle Scholar
  52. 52.
    Giacchetti G, Faloia E, Mariniello B, Sardu C, Gatti C, Camilloni MA, Guerrieri M, Mantero F. Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens 2002; 15:381–388.PubMedGoogle Scholar
  53. 53.
    Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, WaddenT. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998; 83:2907–2910.PubMedGoogle Scholar
  54. 54.
    Itoh K, Imai K, Masuda T, Abe S, Tanaka M, Koga R, Itoh H, Matsuyama T, Nakamura M. Relationship between changes in serum leptin levels and blood pressure after weight loss. Hypertens Res 2002; 25:881–886.PubMedGoogle Scholar
  55. 55.
    Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functionsin obese women after weight loss over one year. Circulation 2002; 105:804–809.PubMedGoogle Scholar
  56. 56.
    De Pergola G, Pannacciulli N. Coagulation and fibrinolysis abnormalities in obesity. J Endocrinol Invest 2002; 25:899–904.PubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    Perreault M, Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 2001; 7:1138–1143.PubMedGoogle Scholar
  59. 59.
    Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 1998; 95:7591–7596.PubMedGoogle Scholar
  60. 60.
    Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997; 82:1313–1316.PubMedGoogle Scholar
  61. 61.
    Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. Jama 1999; 282:2131–2135.PubMedGoogle Scholar
  62. 62.
    Weyer C, Yudkin JS, Stehouwer CD, Schalkwijk CG, Pratley RE, Tataranni PA. Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. Atherosclerosis 2002; 161:233–242.PubMedGoogle Scholar
  63. 63.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46:2347–2355.PubMedGoogle Scholar
  64. 64.
    Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 1994; 43:1271–1278.PubMedGoogle Scholar
  65. 65.
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280:E745–751.PubMedGoogle Scholar
  66. 66.
    Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997; 82:4196–4200.PubMedGoogle Scholar
  67. 67.
    van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation inhumans. J Clin Endocrinol Metab 2003; 88:3005–3010.PubMedGoogle Scholar
  68. 68.
    Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 2003; 52:2784–2789.PubMedGoogle Scholar
  69. 69.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Jama 2001; 286:327–334.PubMedGoogle Scholar
  70. 70.
    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; 101:1767–1772.PubMedGoogle Scholar
  71. 71.
    Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. 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 USA 2001; 98:2005–2010.PubMedGoogle Scholar
  72. 72.
    Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270:26746–26749.PubMedGoogle Scholar
  73. 73.
    Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, KadowakiT. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941–946.PubMedGoogle Scholar
  74. 74.
    Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003; 23:85–89.PubMedGoogle Scholar
  75. 75.
    Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. Jama 2004; 291:1730–1737.PubMedGoogle Scholar
  76. 76.
    Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001; 50:1126–1133.PubMedGoogle Scholar
  77. 77.
    Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Tomita M, Kimura S, Ito C, Froguel P, Kadowaki T. 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.PubMedGoogle Scholar
  78. 78.
    Kondo H, Shimomura I, Matsukawa Y, Kumada M, Takahashi M, Matsuda M, Ouchi N, Kihara S, Kawamoto T, Sumitsuji S, Funahashi T, Matsuzawa Y. Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 2002; 51:2325–2328.PubMedGoogle Scholar
  79. 79.
    Takahashi M, Arita Y, Yamagata K, Matsukawa Y, Okutomi K, Horie M, Shimomura I, Hotta K, Kuriyama H, Kihara S, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord 2000; 24:861–868.PubMedGoogle Scholar
  80. 80.
    Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000; 97:14478–14483.PubMedGoogle Scholar
  81. 81.
    Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 2002; 360:57–58.PubMedGoogle Scholar
  82. 82.
    Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2003; 16:72–75.PubMedGoogle Scholar
  83. 83.
    Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002; 13:134–141.PubMedGoogle Scholar
  84. 84.
    Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T,Funahashi T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 2002; 106:2767–2770.PubMedGoogle Scholar
  85. 85.
    Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001; 103:1057–1063.PubMedGoogle Scholar
  86. 86.
    Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 2004; 109:2046–2049.PubMedGoogle Scholar
  87. 87.
    Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003; 278:45021–45026.PubMedGoogle Scholar
  88. 88.
    Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun 2004; 314:415–419.PubMedGoogle Scholar
  89. 89.
    Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibitedby interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun2003; 301:1045–1050.PubMedGoogle Scholar
  90. 90.
    Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004; 279:1304–1309.PubMedGoogle Scholar
  91. 91.
    Brekke HK, Lenner RA, Taskinen MR, Mansson JE, Funahashi T, Matsuzawa Y, Jansson PA. Lifestyle modification improves risk factors in type 2 diabetes relatives. Diabetes Res Clin Pract 2005; 68:18–28.PubMedGoogle Scholar
  92. 92.
    Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 2003; 42:76–81.PubMedGoogle Scholar
  93. 93.
    Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, Kang MH, Ahn TH, Choi IS, Shin EK. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 2004; 110:3687–3692.PubMedGoogle Scholar
  94. 94.
    Nielsen S, Lihn AS, Ostergaard T, Mogensen CE, Schmitz O. Increased plasma adiponectin in losartan-treated type 1 diabetic patients. a mediator of improved insulin sensitivity? Horm Metab Res 2004; 36:194–196.PubMedGoogle Scholar
  95. 95.
    Koh KK, Han SH, Quon MJ, Yeal Ahn J, Shin EK. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care 2005; 28:1419–1424.PubMedGoogle Scholar
  96. 96.
    Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, anadipose-derived protein. Diabetes 2001; 50:2094–2099.PubMedGoogle Scholar
  97. 97.
    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269:543–546.PubMedGoogle Scholar
  98. 98.
    Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379:632–635.PubMedGoogle Scholar
  99. 99.
    Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, FeiH, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1:1155–1161.PubMedGoogle Scholar
  100. 100.
    Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, BooneT, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269:540–543.PubMedGoogle Scholar
  101. 101.
    Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996; 271:994–996.PubMedGoogle Scholar
  102. 102.
    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392:398–401.PubMedGoogle Scholar
  103. 103.
    Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O’Rahilly S. Partial leptin deficiency and human adiposity. Nature 2001; 414:34–35.PubMedGoogle Scholar
  104. 104.
    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387:903–908.PubMedGoogle Scholar
  105. 105.
    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, PrenticeAM, Hughes IA, McCamish MA, O’Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341:879–884.PubMedGoogle Scholar
  106. 106.
    Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O’Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002; 110:1093–1103.PubMedGoogle Scholar
  107. 107.
    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292–295.PubMedGoogle Scholar
  108. 108.
    Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 2004; 145:4880–4889.PubMedGoogle Scholar
  109. 109.
    Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, WagnerAJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346:570–578.PubMedGoogle Scholar
  110. 110.
    Minokoshi Y, Kahn BB. Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans 2003; 31:196–201.PubMedGoogle Scholar
  111. 111.
    Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8:1288–1295.PubMedGoogle Scholar
  112. 112.
    Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3:340–351.PubMedGoogle Scholar
  113. 113.
    Luo JD, Zhang GS, Chen MS. Leptin and cardiovascular diseases. Timely Top Med Cardiovasc Dis 2005; 9:E34.PubMedGoogle Scholar
  114. 114.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409:307–312.PubMedGoogle Scholar
  115. 115.
    McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S. Resistin, central obesity, and type 2 diabetes. Lancet 2002; 359:46–47.PubMedGoogle Scholar
  116. 116.
    Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, JonesR, Zhu Q, Considine RV. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 2003; 88:5452–5455.PubMedGoogle Scholar
  117. 117.
    Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, SchererPE, Rossetti L. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 2004; 114:232–239.PubMedGoogle Scholar
  118. 118.
    Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest 2003; 111:225–230.PubMedGoogle Scholar
  119. 119.
    Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, WangJ, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L, Lazar MA. Regulation of fasted blood glucose by resistin. Science 2004; 303:1195–1198.PubMedGoogle Scholar
  120. 120.
    Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adiposetissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001; 276:11252–11256.PubMedGoogle Scholar
  121. 121.
    Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, PlumptonC, Macphee CH, Smith SA. Resistin is expressed in human macrophagesand directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 2003; 300:472–476.PubMedGoogle Scholar
  122. 122.
    Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 2001; 50:2199–2202.PubMedGoogle Scholar
  123. 123.
    Banerjee RR, Lazar MA. Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Biol Chem 2001; 276:25970–25973.PubMedGoogle Scholar
  124. 124.
    Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. Disulfide-dependent multimeric assembly of resistin family hormones. Science 2004; 304:1154–1158.PubMedGoogle Scholar
  125. 125.
    Yang RZ, Huang Q, Xu A, McLenithan JC, Eisen JA, Shuldiner AR, Alkan S, Gong DW. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun 2003; 310:927–935.PubMedGoogle Scholar
  126. 126.
    Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 2003; 108:736–740.PubMedGoogle Scholar
  127. 127.
    Calabro P, Samudio I, Willerson JT, Yeh ET. Resistin promotessmooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 2004; 110:3335–3340.PubMedGoogle Scholar
  128. 128.
    Burnett MS, Lee CW, Kinnaird TD, Stabile E, Durrani S, Dullum MK, Devaney JM, Fishman C, Stamou S, Canos D, Zbinden S, Clavijo LC, Jang GJ, Andrews JA, Zhu J, Epstein SE. The potential role of resistin in atherogenesis. Atherosclerosis 2005; 182:241–248.PubMedGoogle Scholar
  129. 129.
    Adeghate E. An update on the biology and physiology of resistin. Cell Mol Life Sci 2004; 61:2485–2496.PubMedGoogle Scholar
  130. 130.
    Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285:561–564.PubMedGoogle Scholar
  131. 131.
    Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M. Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun 2003; 300:674–678.PubMedGoogle Scholar
  132. 132.
    Utzschneider KM, Carr DB, Tong J, Wallace TM, Hull RL, Zraika S, Xiao Q, Mistry JS, Retzlaff BM, Knopp RH, Kahn SE. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia 2005; 48:2330–2333.PubMedGoogle Scholar
  133. 133.
    Lee JH, Bullen JW Jr, Stoyneva VL, Mantzoros CS. Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia. Am J Physiol Endocrinol Metab 2005; 288:E625–632.PubMedGoogle Scholar
  134. 134.
    Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 2004; 53:1671–1679.PubMedGoogle Scholar
  135. 135.
    Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P. Changes in glycemia by leptin administration or high-fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis. Endocrinology 2004; 145:2206–2213.PubMedGoogle Scholar
  136. 136.
    Kim KH, Zhao L, Moon Y, Kang C, Sul HS. Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity. Proc Natl Acad Sci USA 2004; 101:6780–6785.PubMedGoogle Scholar
  137. 137.
    Schaffler A, Buchler C, Muller-Ladner U, Herfarth H, Ehling A, Paul G, Scholmerich J, Zietz B. Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus. Horm Metab Res 2004; 36:702–707.PubMedGoogle Scholar
  138. 138.
    Vendrell J, Broch M, Vilarrasa N, Molina A, Gomez JM, Gutierrez C, Simon I, Soler J, Richart C. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obes Res 2004; 12:962–971.PubMedGoogle Scholar
  139. 139.
    Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A, Saruta T. Correlation between serum resistin level and adiposity in obese individuals. Obes Res 2003; 11:997–1001.PubMedGoogle Scholar
  140. 140.
    Yannakoulia M, Yiannakouris N, Bluher S, Matalas AL, Klimis-Zacas D, Mantzoros CS. Body fat mass and macronutrient intake inrelation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab 2003; 88:1730–1736.PubMedGoogle Scholar
  141. 141.
    McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S. Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab 2003; 88:6098–6106.PubMedGoogle Scholar
  142. 142.
    Zhang J, Qin Y, Zheng X, Qiu J, Gong L, Mao H, Jia W, Guo J. [The relationship between human serum resistin level and body fat content, plasma glucose as well as blood pressure]. Zhonghua Yi Xue Za Zhi 2002; 82:1609–1612.PubMedGoogle Scholar
  143. 143.
    McTernan PG, McTernan CL, Chetty R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S. Increased resistin gene and protein expression in human abdominal adipose tissue. J Clin Endocrinol Metab 2002; 87:2407.PubMedGoogle Scholar
  144. 144.
    Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S. Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines. Metabolism 2004; 53:430–434.PubMedGoogle Scholar
  145. 145.
    Maebuchi M, Machidori M, Urade R, Ogawa T, Moriyama T. Low resistin levels in adipose tissues and serum in high-fat fed mice and genetically obese mice: development of an ELISA system forquantification of resistin. Arch Biochem Biophys 2003; 416:164–170.PubMedGoogle Scholar
  146. 146.
    Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem 2001; 276:6343–6349.PubMedGoogle Scholar
  147. 147.
    Lahlou N, Clement K, Carel JC, Vaisse C, Lotton C, Le Bihan Y, Basdevant A, Lebouc Y, Froguel P, Roger M, Guy-Grand B. Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass. Diabetes 2000; 49:1347–1352.PubMedGoogle Scholar
  148. 148.
    Winkler G, Kiss S, Keszthelyi L, Sapi Z, Ory I, Salamon F, Kovacs M, Vargha P, Szekeres O, Speer G, Karadi I, Sikter M, Kaszas E, Dworak O, Gero G, Cseh K. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol 2003; 149:129–135.PubMedGoogle Scholar
  149. 149.
    Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectionaland interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 2003; 88:4848–4856.PubMedGoogle Scholar
  150. 150.
    Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 2003; 149:331–335.PubMedGoogle Scholar
  151. 151.
    Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab 2004; 89:1844–1848.PubMedGoogle Scholar
  152. 152.
    Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 2003; 52:1611–1618.PubMedGoogle Scholar
  153. 153.
    Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta 2004; 339:57–63.PubMedGoogle Scholar
  154. 154.
    Pfutzner A, Langenfeld M, Kunt T, Lobig M, Forst T. Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin Lab 2003; 49:571–576.PubMedGoogle Scholar
  155. 155.
    Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, Cho YM, Park YJ, Kim SY, Lee HK, Park KS. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab 2004; 89:150–156.PubMedGoogle Scholar
  156. 156.
    Ridker PM, Koenig W, Fuster V. C-reactive protein and coronary heart disease. N Engl J Med 2004; 351:295–298; author reply 295–298.Google Scholar
  157. 157.
    Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. Jama 2003; 289:1799–1804.PubMedGoogle Scholar
  158. 158.
    Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M,D’ Andrea F, Giugliano D. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. Jama 2004; 292:1440–1446PubMedGoogle Scholar
  159. 159.
    Obisesan TO, Leeuwenburgh C, Phillips T, Ferrell RE, Phares DA, Prior SJ, Hagberg JM. C-reactive protein genotypes affect baseline, but not exercise training-induced changes, in C-reactive protein levels. Arterioscler Thromb Vasc Biol 2004; 24:1874–1879.PubMedGoogle Scholar
  160. 160.
    Okita K, Nishijima H, Murakami T, Nagai T, Morita N, Yonezawa K, Iizuka K, Kawaguchi H, Kitabatake A. Can exercise training with weight loss lower serum C-reactive protein levels? Arterioscler Thromb Vasc Biol 2004; 24:1868–1873.PubMedGoogle Scholar
  161. 161.
    Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 2003; 107:671–674.PubMedGoogle Scholar
  162. 162.
    Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO, Kropf J, Kerber S, Breithardt G, Assmann G, Cullen P. Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol 1999; 19:2355–2363.PubMedGoogle Scholar
  163. 163.
    Fyfe AI, Rothenberg LS, DeBeer FC, Cantor RM, Rotter JI, Lusis AJ. Association between serum amyloid A proteins and coronary artery disease: evidence from two distinct arteriosclerotic processes. Circulation 1997; 96:2914–2919.PubMedGoogle Scholar
  164. 164.
    Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836–843.PubMedGoogle Scholar
  165. 165.
    Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events(CARE) Investigators. Circulation 1998; 98:839–844.PubMedGoogle Scholar
  166. 166.
    Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 2:800–803.PubMedGoogle Scholar
  167. 167.
    Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251:471–476.PubMedGoogle Scholar
  168. 168.
    Boucher J, Masri B, Daviaud D, Gesta S, Guigne C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpene C, Audigier Y, Saulnier-Blache JS, Valet P. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005; 146:1764–1771.PubMedGoogle Scholar
  169. 169.
    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 2005; 307:426–430.PubMedGoogle Scholar
  170. 170.
    Hirai K, Hussey HJ, Barber MD, Price SA, Tisdale MJ. Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients. Cancer Res 1998; 58:2359–2365.PubMedGoogle Scholar
  171. 171.
    Todorov PT, McDevitt TM, Meyer DJ, Ueyama H, Ohkubo I, Tisdale MJ. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res 1998; 58:2353–2358.PubMedGoogle Scholar
  172. 172.
    Russell ST, Hirai K, Tisdale MJ. Role of beta3-adrenergic receptors in the action of a tumour lipid mobilizing factor. Br J Cancer 2002; 86:424–428.PubMedGoogle Scholar
  173. 173.
    Bing C, Bao Y, Jenkins J, Sanders P, Manieri M, Cinti S, TisdaleMJ, Trayhurn P. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc Natl Acad Sci USA 2004; 101:2500–2505.PubMedGoogle Scholar
  174. 174.
    Bao Y, Yamano Y, Morishima I. A novel lebocin-like gene from eri-silkworm, Samia cynthia ricini, that does not encode the antibacterial peptide lebocin. Comp Biochem Physiol B Biochem MolBiol 2005; 140:127–131.PubMedGoogle Scholar
  175. 175.
    Gohda T, Makita Y, Shike T, Tanimoto M, Funabiki K, Horikoshi S, Tomino Y. Identification of epistatic interaction involved in obesity using the KK/Ta mouse as a Type 2 diabetes model: is Zn-alpha2 glycoprotein-1 a candidate gene for obesity? Diabetes 2003; 52:2175–2181.PubMedGoogle Scholar
  176. 176.
    Hug C, Lodish HF. Medicine. Visfatin: a new adipokine. Science2005; 307:366–367.PubMedGoogle Scholar
  177. 177.
    Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 2001; 280:E827–847.PubMedGoogle Scholar
  178. 178.
    Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001; 60:329–339.PubMedGoogle Scholar
  179. 179.
    Dietze D, Koenen M, Rohrig K, Horikoshi H, Hauner H, Eckel J. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 2002; 51:2369–2376.PubMedGoogle Scholar
  180. 180.
    Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA,Bornstein SR. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci USA 2003; 100:14211–14216.PubMedGoogle Scholar
  181. 181.
    Rayner DV, Trayhurn P. Regulation of leptin production: sympathetic nervous system interactions. J Mol Med 2001; 79:8–20.PubMedGoogle Scholar
  182. 182.
    De Ceuninck F, Dassencourt L, Anract P. The inflammatory side of human chondrocytes unveiled by antibody microarrays. Biochem Biophys Res Commun 2004; 323:960–969.PubMedGoogle Scholar
  183. 183.
    Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Wolsk-Petersen E, Febbraio M. The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc Nutr Soc 2004; 63:263–267.PubMedGoogle Scholar
  184. 184.
    Pedersen BK, Steensberg A, Fischer C, Keller C, Ostrowski K, Schjerling P. Exercise and cytokines with particular focus on muscle-derived IL-6. Exerc Immunol Rev 2001; 7:18–31.PubMedGoogle Scholar
  185. 185.
    Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47:507–514.PubMedGoogle Scholar
  186. 186.
    Kallen CB, Lazar MA. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1996; 93:5793–5796.PubMedGoogle Scholar
  187. 187.
    Greenberg AS. The expanding scope of the metabolic syndrome and implications for the management of cardiovascular risk in type 2 diabetes with particular focus on the emerging role of the thiazolidinediones. J Diabetes Complications 2003; 17:218–228.PubMedGoogle Scholar
  188. 188.
    Calabro P, Samudio I, Safe SH, Willerson JT, Yeh ET. Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation bya new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects. J Vasc Res 2005; 42:509–516.PubMedGoogle Scholar
  189. 189.
    Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106:679–684.PubMedGoogle Scholar
  190. 190.
    Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002; 277:25226–25232.PubMedGoogle Scholar
  191. 191.
    Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, MakimattilaS, Yki-Jarvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004; 53:2169–2176.PubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Paolo Calabro
    • 1
    • 2
  • Edward T. H. Yeh
    • 2
    • 3
  1. 1.Division of Cardiology, Department of Cardiothoracic SciencesSecond University of NaplesItaly
  2. 2.The Brown Foundation Institute of Molecular Medicine for the Prevention of Human DiseasesThe University of Texas-Houston Health Science CenterHoustonTexas
  3. 3.The Department of CardiologyThe University of Texas-M.D. Anderson Cancer CenterHoustonTexas

Personalised recommendations