Adipose tissue, inflammation and cardiovascular disease.

Obesity has become a very frequent condition with important consequences for the health of affected individuals. Current evidence shows that the excess of adipose tissue as observed in obesity is responsible for secreting inflammatory mediators in a deregulated manner, thus inducing a chronic state of systemic low-grade inflammation that underlies the metabolic and cardiovascular outcomes in these populations. This article reviews the state of the art regarding mediators produced in the adipose tissue, their roles in the pathophysiology of obesity-associated insulin resistance and diabetes, and finally, tries to build a bridge between these mechanistically oriented insights and clinical practice.

[1]  A. Selwyn,et al.  Effects of statins on inflammation in patients with acute and chronic coronary syndromes. , 2003, The American journal of cardiology.

[2]  Hitoshi Nishizawa,et al.  Reciprocal Association of C-Reactive Protein With Adiponectin in Blood Stream and Adipose Tissue , 2003, Circulation.

[3]  R. Marfella,et al.  Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functions in Obese Women After Weight Loss Over One Year , 2002, Circulation.

[4]  G. Lowe,et al.  The relationship between infection, inflammation, and cardiovascular disease: an overview. , 2001, Annals of periodontology.

[5]  K. Esposito,et al.  Effect of liposuction on insulin resistance and vascular inflammatory markers in obese women. , 2004, British journal of plastic surgery.

[6]  J. Fung,et al.  Attenuation of aortic graft arteriosclerosis by systemic administration of Allotrap peptide RDP58 , 2002, Transplant international : official journal of the European Society for Organ Transplantation.

[7]  J. Kaski,et al.  Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease , 2004 .

[8]  C. Tsigos,et al.  Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. , 1999, Metabolism: clinical and experimental.

[9]  A. Localio,et al.  Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. , 2004, The Journal of clinical endocrinology and metabolism.

[10]  R. Nosadini,et al.  The role of the renin angiotensin hormonal system in the metabolic syndrome and type 2 diabetes. , 2004, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[11]  S. Manzi,et al.  Update on vascular disease in systemic lupus erythematosus , 2003, Current opinion in rheumatology.

[12]  H. Hauner,et al.  Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1 , 2004, International Journal of Obesity.

[13]  S. Verma,et al.  Hyperglycemia potentiates the proatherogenic effects of C-reactive protein: reversal with rosiglitazone. , 2003, Journal of molecular and cellular cardiology.

[14]  L Wood,et al.  Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. , 2001, American journal of physiology. Endocrinology and metabolism.

[15]  S. Haffner,et al.  Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus , 2002, Circulation.

[16]  E. Poehlman,et al.  Weight Loss Reduces C-Reactive Protein Levels in Obese Postmenopausal Women , 2002, Circulation.

[17]  M. Boscaro,et al.  Adipose Tissue as an Endocrine Organ? A Review of Recent Data Related to Cardiovascular Complications of Endocrine Dysfunctions , 2004, Clinical and experimental hypertension.

[18]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-α function , 1997, Nature.

[19]  S. Yamashita,et al.  Enhanced expression of PAI–1 in visceral fat: Possible contributor to vascular disease in obeisty , 1996, Nature Medicine.

[20]  S. Blankenberg,et al.  Impact of Viral and Bacterial Infectious Burden on Long-Term Prognosis in Patients With Coronary Artery Disease , 2001, Circulation.

[21]  J. Huttunen,et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. , 1987, The New England journal of medicine.

[22]  R. Mortensen.  C-reactive protein, inflammation, and innate immunity , 2001, Immunologic research.

[23]  J. Peschon,et al.  Accelerated Atherosclerosis in Mice Lacking Tumor Necrosis Factor Receptor p55* , 1996, The Journal of Biological Chemistry.

[24]  A. Whitehead,et al.  Serum amyloid A, the major vertebrate acute-phase reactant. , 1999, European journal of biochemistry.

[25]  J. Engel,et al.  Structure-Function Studies of the Adipocyte-secreted Hormone Acrp30/Adiponectin , 2003, The Journal of Biological Chemistry.

[26]  P. Scherer,et al.  Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/en.2003-0580 Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis , 2022 .

[27]  S. Kihara,et al.  Obesity, adiponectin and vascular inflammatory disease , 2003, Current opinion in lipidology.

[28]  C. Mantzoros,et al.  Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. , 2004, Diabetes care.

[29]  D. Furst,et al.  Anti–tumor necrosis factor α therapy and heart failure: What have we learned and where do we go from here? , 2004 .

[30]  Remi Rabasa-Lhoret,et al.  Metabolic and body composition factors in subgroups of obesity: what do we know? , 2004, The Journal of clinical endocrinology and metabolism.

[31]  M. Tendera,et al.  Role of antiplatelet drugs in the prevention of cardiovascular events. , 2003, Thrombosis research.

[32]  S. Kihara,et al.  Adiponectin Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice , 2002, Circulation.

[33]  A. Madan,et al.  Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. , 2004, Endocrinology.

[34]  D. Giugliano,et al.  Effect of a multidisciplinary program of weight reduction on endothelial functions in obese women , 2003, Journal of endocrinological investigation.

[35]  S. Blankenberg,et al.  Impact of Infectious Burden on Progression of Carotid Atherosclerosis , 2002, Stroke.

[36]  L. Hovgaard,et al.  Inhibition of Tumor Necrosis Factor-&agr; Reduces Atherosclerosis in Apolipoprotein E Knockout Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[37]  Inflammatory Markers and Risk of Heart Failure in Elderly Subjects Without Prior Myocardial Infarction: The Framingham Heart Study , 2003 .

[38]  R. Chakrabarti,et al.  Blood Fibrinolytic Activity in Diabetes Mellitus and Its Bearing on Ischaemic Heart Disease and Obesity , 1963, British medical journal.

[39]  V. Somers,et al.  Independent Association Between Plasma Leptin and C-Reactive Protein in Healthy Humans , 2004, Circulation.

[40]  L. Kuller,et al.  The Chronic Inflammatory Hypothesis for the Morbidity Associated with Morbid Obesity: Implications and Effects of Weight Loss , 2004, Obesity surgery.

[41]  B. Staels,et al.  Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. , 1999, Circulation research.

[42]  Paul M Ridker,et al.  Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? , 2004, Circulation.

[43]  John A Wagner,et al.  Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity* , 2004, Journal of Biological Chemistry.

[44]  P. Froguel,et al.  Impaired Multimerization of Human Adiponectin Mutants Associated with Diabetes , 2003, Journal of Biological Chemistry.

[45]  J. Egido,et al.  Inflammation and angiotensin II. , 2003, The international journal of biochemistry & cell biology.

[46]  I. Kroop,et al.  Level of C-Reactive Protein as a Measure of Acute Myocardial Infarction.∗ , 1954, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[47]  L. Niskanen,et al.  Development of diabetes is retarded by ACE inhibition in hypertensive patients – a subanalysis of the Captopril Prevention Project (CAPPP) , 2004, Journal of hypertension.

[48]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[49]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[50]  B. Goldstein,et al.  Adiponectin: A novel adipokine linking adipocytes and vascular function. , 2004, The Journal of clinical endocrinology and metabolism.

[51]  M. Di Napoli,et al.  Angiotensin-Converting Enzyme Inhibitor Use Is Associated With Reduced Plasma Concentration of C-Reactive Protein in Patients With First-Ever Ischemic Stroke , 2003, Stroke.

[52]  G. Hotamisligil,et al.  Inflammatory pathways and insulin action , 2003, International Journal of Obesity.

[53]  D. Harrison,et al.  The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis , 2002 .

[54]  B. Saltin,et al.  Searching for the exercise factor: is IL-6 a candidate? , 2004, Journal of Muscle Research & Cell Motility.

[55]  T. Hedner,et al.  A common polymorphism in the interleukin-6 gene promoter is associated with overweight , 2004, International Journal of Obesity.

[56]  Lan Li,et al.  C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice , 2004, Circulation.

[57]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[58]  Anoop Misra,et al.  Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. , 2003, Nutrition.

[59]  Tzung-Dau Wang,et al.  Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome. , 2004, The American journal of cardiology.

[60]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[61]  W. Haynes,et al.  Obesity-related hypertension: Is there a role for selective leptin resistance? , 2004, Current hypertension reports.

[62]  A. Itai,et al.  A novel IKKbeta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance. , 2004, Biochemical and biophysical research communications.

[63]  R. Ahima,et al.  Adipose Tissue as an Endocrine Organ , 2006, Obesity.

[64]  G. Davı̀,et al.  Platelet activation in obese women: role of inflammation and oxidant stress. , 2002, JAMA.

[65]  Sidney C. Smith,et al.  Periodontal disease in patients with acute myocardial infarction: prevalence and contribution to elevated C-reactive protein levels. , 2004, American heart journal.

[66]  A. Takeshita,et al.  Essential Role of Vascular Endothelial Growth Factor in Angiotensin II–Induced Vascular Inflammation and Remodeling , 2004, Hypertension.

[67]  James T. Willerson,et al.  Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells , 2000, Circulation.

[68]  Alessandro Pontillo,et al.  Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. , 2003, JAMA.

[69]  Andrew R. Coggan,et al.  Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. , 2004, The New England journal of medicine.

[70]  Xiao Man Yang,et al.  Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? , 2002, Diabetes.

[71]  H. Drexler,et al.  Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. , 2004, Journal of the American College of Cardiology.

[72]  P. Ridker.  Clinical application of C-reactive protein for cardiovascular disease detection and prevention. , 2003, Circulation.

[73]  V. Sánchez-Margalet,et al.  Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action , 2003, Clinical and experimental immunology.

[74]  J. Rutledge,et al.  Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. , 2002, Physiological genomics.

[75]  A. Steensberg.  The role of IL-6 in exercise-induced immune changes and metabolism. , 2003, Exercise immunology review.

[76]  S. Ogawa,et al.  C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q-wave acute myocardial infarction. , 1997, Circulation.

[77]  S. Shoelson,et al.  Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance , 2003, International Journal of Obesity.

[78]  N. Sattar,et al.  Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians , 2001, International Journal of Obesity.

[79]  M. Margaglione,et al.  Low-grade inflammation may play a role in the etiology of the metabolic syndrome in patients with coronary heart disease: the HIFMECH study. , 2004, Metabolism: clinical and experimental.

[80]  K. McCormick,et al.  White adipocyte vascular endothelial growth factor: regulation by insulin. , 2002, Endocrinology.

[81]  Jun Ren,et al.  Leptin and hyperleptinemia - from friend to foe for cardiovascular function. , 2004, The Journal of endocrinology.

[82]  H. Markus,et al.  Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[83]  J. Berger,et al.  Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation , 2003, International Journal of Obesity.

[84]  D. Loskutoff,et al.  The adipocyte and hemostatic balance in obesity: studies of PAI-1. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[85]  R. Leboeuf,et al.  Loss of Lymphotoxin-α but Not Tumor Necrosis Factor-α Reduces Atherosclerosis in Mice* , 2002, The Journal of Biological Chemistry.

[86]  Haiyan Xu,et al.  Transmembrane Tumor Necrosis Factor (TNF)-α Inhibits Adipocyte Differentiation by Selectively Activating TNF Receptor 1* , 1999, The Journal of Biological Chemistry.

[87]  K. Shirai.  Obesity as the core of the metabolic syndrome and the management of coronary heart disease , 2004, Current medical research and opinion.

[88]  H. Bujo,et al.  Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects , 2003, Diabetologia.

[89]  Mireille André,et al.  Preadipocyte Conversion to Macrophage , 2003, The Journal of Biological Chemistry.

[90]  N. Cook,et al.  Clinical Usefulness of Very High and Very Low Levels of C-Reactive Protein Across the Full Range of Framingham Risk Scores , 2004, Circulation.

[91]  M. Woodward,et al.  A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C‐reactive protein following myocardial infarction: the CADET trial , 2004, Journal of thrombosis and haemostasis : JTH.

[92]  S. Ishibashi,et al.  Decrease in serum C-reactive protein levels by troglitazone is associated with pretreatment insulin resistance, but independent of its effect on glycemia, in type 2 diabetic subjects. , 2004, Diabetes research and clinical practice.

[93]  I. Sakuma,et al.  Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. , 2004, Atherosclerosis.

[94]  S. Mudaliar,et al.  Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. , 2002, Diabetes care.

[95]  D. Loskutoff,et al.  Leptin Promotes Vascular Remodeling and Neointimal Growth in Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[96]  T. Ishimitsu,et al.  Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors. , 2003, Atherosclerosis.

[97]  B. Okopień,et al.  Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. , 1998, International journal of clinical pharmacology and therapeutics.

[98]  Cynthia J. Girman,et al.  Plasma adiponectin levels and risk of myocardial infarction in men. , 2004, JAMA.

[99]  J. Sowers.  Obesity as a cardiovascular risk factor. , 2003, The American journal of medicine.

[100]  G. Zaloga,et al.  C-reactive protein: from innocent bystander to pivotal mediator of atherosclerosis. , 2004, The American journal of medicine.

[101]  F. Lönnqvist,et al.  Mapping of Early Signaling Events in Tumor Necrosis Factor-α-mediated Lipolysis in Human Fat Cells* , 2002, The Journal of Biological Chemistry.

[102]  A. Nanji,et al.  Relationship between body weight and total leukocyte count in morbid obesity. , 1985, American journal of clinical pathology.

[103]  B. Spiegelman,et al.  Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. , 1992, The Journal of biological chemistry.

[104]  G. Pergola,et al.  Coagulation and fibrinolysis abnormalities in obesity , 2002, Journal of endocrinological investigation.

[105]  M. Lisanti,et al.  The Lipopolysaccharide-activated Toll-like Receptor (TLR)-4 Induces Synthesis of the Closely Related Receptor TLR-2 in Adipocytes* , 2000, The Journal of Biological Chemistry.

[106]  Paul M. Ridker,et al.  Inflammation as a Cardiovascular Risk Factor , 2004, Circulation.

[107]  J. Rolff,et al.  Invertebrate Ecological Immunology , 2003, Science.

[108]  Vesa Manninen,et al.  Joint Effects of Serum Triglyceride and LDL Cholesterol and HDL Cholesterol Concentrations on Coronary Heart Disease Risk in the Helsinki Heart Study: Implications for Treatment , 1992, Circulation.

[109]  P. Arner,et al.  Altered Tumor Necrosis Factor-α (TNF-α) Processing in Adipocytes and Increased Expression of Transmembrane TNF-α in Obesity , 2002 .

[110]  Sebastian Schneeweiss,et al.  Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults , 2004, Circulation.

[111]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[112]  L. Heilbronn,et al.  Energy Restriction and Weight Loss on Very-Low-Fat Diets Reduce C-Reactive Protein Concentrations in Obese, Healthy Women , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[113]  A. Greenberg,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Omental and Subcutaneous Adipose Tissues of Obese Subjects Release Interleukin-6: Depot Difference and Regulation by Glucocorticoid* , 1997 .

[114]  S. Kihara,et al.  Adiponectin Specifically Increased Tissue Inhibitor of Metalloproteinase-1 Through Interleukin-10 Expression in Human Macrophages , 2004, Circulation.

[115]  Claude Lenfant,et al.  Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[116]  H. Hauner,et al.  HMG-CoA Reductase Inhibitor Cerivastatin Inhibits Interleukin-6 Expression and Secretion in Human Adipocytes , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[117]  O. Pachinger,et al.  Vascular endothelial growth factor: angiogenesis, atherogenesis or both? , 2001, Journal of the American College of Cardiology.

[118]  D. Simonson,et al.  Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. , 2003, Diabetes care.

[119]  Philippe Froguel,et al.  Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation* , 2002, The Journal of Biological Chemistry.

[120]  P. Persson,et al.  Role of leptin and leptin receptor in inflammation. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[121]  M. Lisanti,et al.  Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. , 2004, American journal of physiology. Endocrinology and metabolism.

[122]  S. Kihara,et al.  Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells* , 2004, Journal of Biological Chemistry.

[123]  E. Minar,et al.  Impact of Weight Loss on Inflammatory Proteins and Their Association With the Insulin Resistance Syndrome in Morbidly Obese Patients , 2003, Arteriosclerosis, thrombosis, and vascular biology.