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This Review is part of a thematic series on Adipocyte Signaling in the Cardiovascular System, which includes the
following articles:
Adipose Tissue, Inflammation, and Cardiovascular Disease
Diabetic Cardiomyopathy
Adipocyte Signaling and Lipid Homeostasis
Adipocyte Signaling and the Vasculature
PPAR Activation and Effects on the Vasculature
Original received December 29, 2004; revision received March 9, 2005; accepted March 15, 2005.
From the Departments of Cell Biology (A.H.B., P.E.S.), Medicine (P.E.S.), Division of Endocrinology, and Diabetes Research and Training Center
(P.E.S.), Albert Einstein College of Medicine, Bronx, NY. A.H. Bergs present address: Department of Pathology, Brigham and Womens Hospital, 75
Francis St, Boston, MA 02115.
Correspondence to Philipp E. Scherer, Albert Einstein College of Medicine 1300 Morris Park Ave, Bronx, NY 10461. E-mail scherer@aecom.yu.edu
2005 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
DOI: 10.1161/01.RES.0000163635.62927.34
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Circulation Research
esis but is instead an important contributor. Obese hypertrophic adipocytes and stromal cells within adipose tissue
directly augment systemic inflammation. This increase in
systemic inflammation mediates multiple pathogenic mechanisms in the well-known but poorly understood associations
between obesity, cardiovascular pathology, and the comorbidities such as dyslipidemia, type 2 diabetes mellitus, hypertension, and the metabolic syndrome. Here we review the
evidence that adipose tissue is indeed an organ with properties that make it a significant contributor to systemic inflammation. We also review the studies linking obesity to subclinical inflammation, mention the studies showing that this
increase in inflammation translates into accelerated atherogenesis, and illustrate these mechanisms by dissecting specific secreted inflammatory factors implicated in mediating
these connections. Finally, we briefly discuss clinical implications of these recent discoveries for our treatment of
obesity- and inflammation-associated diseases.
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C-Reactive Protein
The first observations of the well-known association between
CRP and cardiac risk was in 1954, when it was found that after
myocardial infarction, there was a dramatic rise in circulating
CRP levels and the amplitude of this rise correlated with poor
prognosis.31,32 Subsequently, it was also found that preinfarctelevated CRP levels correlated with an increased risk of future
cardiac events as well. Not only were preinfarction CRP levels
correlated with increased risk for later adverse cardiac events
and sudden death, elevated circulating levels of IL-6, IL-18,
1-antitrypsin, SAA3, and ICAM-1 were as well,33,34 and
increased IL-6 levels have been correlated recently with increased risk of congestive heart failure development in elderly
patients even before evidence of CVD.33
There is currently great excitement surrounding the acutephase reactant CRP for the insights it is providing into the
etiologic relationships between inflammation and clinical vasculopathic syndromes, its usefulness as a clinical marker, and
evidence for a direct pathogenic involvement. Elevated CRP
levels are unquestionably associated with obesity and increased
risk of CVD. Numerous additional studies have further strengthened the association of elevated CRP levels with nearly all the
important cardiovascular risk factors, including insulin resistance and diabetes, metabolic syndrome, hypertension, smoking,
and dyslipidemia.35 Numerous ongoing studies have demonstrated a linear relationship between circulating levels of CRP
and CVD risk.36 They revealed that elevated CRP levels in obese
patients are not only prognostic for the development of CVD but
also predictive of the risk of progression to type 2 diabetes
mellitus.37 Elevated CRP levels in obesity and the decreases
associated with weight loss provide another suggestive link
between CRP and obesity-associated risks for CVD and diabetes.21,25,38,39 Finally, the contribution of CRP to atherogenesis has
been demonstrated in apolipoprotein E (apoE) deficient mice;
although apoE knockout mice are already predisposed to atherosclerosis, crossing them with transgenic mice overexpressing
CRP significantly exacerbated atherosclerotic progression.40
Most intriguingly, a number of pharmacological interventions
aimed at improving insulin sensitivity (with thiazolidinediones
or metformin), hypertension (angiotensin inhibitors), or cholesterol biosynthesis (statins) have also been shown to cause
significant reductions in CRP levels.34,41 Together, these results
show such reciprocity between all variables that suggest not so
much a linear path of causality but rather a linked matrix with
inflammation and CRP at the nexus.
In addition to epidemiological and mouse model data demonstrating CRP to be a useful clinical marker for CVD risk, there
Interleukin-6
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Angiotensinogen
Angiotensinogen and angiotensin-converting enzymes (ACEs)
are secreted from adipose, mostly from visceral depots.66 Correspondingly, elevated levels of angiotensinogen and AT-II are
found in obese states.67 AT-II has numerous effects on the
endothelium and vascular smooth muscle, including its wellknown vasoconstrictive effects and contributions to hypertension. In addition, AT-II may contribute to local vascular inflammation via induction of endothelial expression of VCAM-1,
ICAM-1, and MCP-1.68 It has also been demonstrated that AT-II
is a potent activator of endothelial proliferation as well. In
addition to its direct effects on vascular components, clinical
trials of angiotensin blocking regimens in patients after coronary
angioplasty have demonstrated that specific inhibition of the
renin-angiotensin axis causes significant decreases in systemic
inflammation, including IL-6, CRP, TNF, and metalloproteinases.69 Thus, the observed secretion and resulting elevated levels
of AT-II in obese states contribute to angiogenesis, hypertension,
and atheromatous changes.67,70
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Leptin
Although leptin is not usually thought of as an inflammatory
cytokine, hyperleptinemia has been shown to be induced by
inflammatory signals such as endotoxin and has important
effects on Th1 immune responses76 and activates blood
monocytes in culture.77 Furthermore, leptin levels are correlated with the CRP and other inflammatory markers in
healthy and morbidly obese subjects.78 Better known is the
role of elevated leptin levels in the obese state.79 Here, leptin
is thought to contribute to insulin resistance and considered to
be one of the links between obesity, insulin resistance, and
atherosclerosis. However, a recent study looking at type 2
diabetics demonstrated that hyperleptinemia is associated
with atherosclerosis independent of insulin resistance.80 Leptin has also been demonstrated to contribute to vasculopathy
via obesity-associated hypertension, not through metabolic
actions, but instead via its action on central sympathoregulatory pathways.81 Finally, leptin plays a role in diet-induced
neointimal thickening after vascular injury.82 These activities,
in addition to possible contributions to atheromatous inflammation through monocyte and Th1 activation, may explain
the epidemiological association between elevated levels and
cardiovascular risk.
Serum Amyloid A3
SAA3 is an acute-phase reactant secreted by many tissues of the
body, including adipocytes, and there is growing evidence that it
may make a significant contribution to atherogenesis. Circulating levels are elevated in obese and diabetic patients because of
induction via inflammatory signal transduction pathways, as
well as activation by hyperglycemia itself.8 The proven and
hypothesized activities of SAA3 include action as a chemoattractant, inducer of remodeling metalloproteinases, and stimulation of T-cell cytokine production.83 It also acts as an apolipoprotein, binding HDL and possibly targeting the deposition of
the transported cholesterols to atheromatous foam cells.83 These
lipoprotein-binding properties of this protein have been suggested to act as a means of absorbing toxic bacterial cell wall
lipids. Whatever the purpose for this protein in infection, in the
context of obesity-induced inflammation, it is thought to promote local inflammation and inappropriate lipid accumulation.
Adiponectin
Adiponectin is an adipocyte secretory protein, the circulating
levels of which are decreased in obese and diabetic states. This
protein has been shown to play a role in liver insulin sensitivity
and whole-body metabolism.6 Adiponectin has been implicated
in cardiovascular health as well, at the very least as a highly
sensitive serum marker for the prediction of future cardiovascular events. Retrospective case-control studies demonstrate that
patients with the highest levels of adiponectin have a dramatically reduced 6-year risk of myocardial infarction compared
with case controls with the lowest adiponectin levels, and this
relationship persists even when controlling for family history,
BMI, alcohol, history of diabetes and hypertension, hemoglobin
A1c, CRP, and lipoprotein levels.84 Animal models also corroborate these observations, showing that adiponectin is particularly
important for preventing diet-induced progression of
atherosclerosis.85,86
The exact mechanism of the antiatherosclerotic activity of adiponectin has not been completely elucidated. The association
between adiponectin levels and cardiovascular risk independent of
other variables suggests that adiponectin mediates direct effects on
vascular health, as opposed to indirect effects through insulin
sensitivity and diabetes. A number of studies have shown direct
effects of adiponectin on endothelial and vascular smooth muscle
cells.87 It has also been hypothesized that adiponectin has
inflammatory-modulating activities, and clinical studies have demonstrated inverse associations between adiponectin levels and serum
markers of inflammation.19 An early article using a truncated
recombinant form of adiponectin suggested that it activates NF-B
in endothelial cells, whereas subsequent articles have found antiinflammatory effects on endothelium and macrophages.88,89 Unfortunately, all of these studies used a recombinant, bacterially produced, truncated form of the protein. Although this fragment is a
form with potential as a pharmacological agent, it differs in its
bioactivity from the endogenous post-translationally modified and
multimerized hormone.90,91 Thus, the conclusions from studies that
exclusively rely on the use of this recombinant trimeric ligand must
be interpreted with caution.
Although it is not clear how or whether adiponectin itself
has anti-inflammatory properties, it is clear that adiponectin
production by adipose can be inhibited by systemic inflammation, at least under some circumstances. Adiponectin
production by adipocytes has been shown to be inhibited by
inflammatory cytokines such as TNF- in vitro.92 This
inhibition may be mediated in part by NF-B signaling. In
vitro studies on cultured adipocytes, as well as in vivo studies
using obese diabetic mice, revealed that inhibition of adipocyte inflammatory NF-B signaling by an IB kinase inhibitor resulted not only in decreased cytokine levels but also
increased adiponectin levels in plasma.93 Thus, IB kinase
inhibition is leading to increased plasma adiponectin levels,
concomitant with an improvement in systemic insulin sensitivity.94 If adiponectin does have anti-inflammatory activities,
they are likely mediated by its principal signaling target, the
AMP-activated protein kinase (AMPK).95 There is evidence
that the truncated bacterial form of adiponectin has antiinflammatory effects on endothelium via AMPK-mediated
modulation of NF-B and Akt/protein kinase B.96 Thus, there
is preliminary evidence that some of the proven antiatheromatous effects of adiponectin may be mediated by antiinflammatory activities acting directly on the vasculature.
In addition to its possible anti-inflammatory properties and
their implications for CVD, it is important to mention the recent
demonstration that adiponectin may also have an important role
in protecting against cardiac hypertrophy in cardiac overload
states such as hypertension, hypertrophic cardiomyopathy, and
ischemic heart disease. Adiponectin was shown in mice to
protect against overload-induced and adrenergically induced
cardiac myocyte hypertrophy, specifically by inhibiting hyper-
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Summary
In the search for mechanisms of obesity-mediated vascular
pathology, mounting evidence has implicated adipocytes and
adipose tissue in the development of a systemic inflammatory
state. Numerous studies demonstrate that circulating mediators of inflammation participate in the mechanisms of vascular insult and atheromatous change. Many of these inflammatory proteins are secreted from adipocytes and adipose tissue,
with dramatically increased amounts of inflammatory proteins and decreased amount of cardioprotective adiponectin
secreted from obese adipose. Secretion of inflammatory
factors from visceral adipose tissue into the portal system and
resulting effects on the liver and systemic inflammation may
be the cause of the tight correlation between increased truncal
obesity and vasculopathic phenomena and the metabolic
syndrome. Studies on antiobesity and anti-inflammatory therapeutic interventions corroborate these casual relationships.
Weight loss correlates with decreased inflammation, the
cardioprotective effects of many of the most popular drug
regimens are correlated with improvements in systemic inflammation, and in a few cases, it has been demonstrated that
the improvements in systemic inflammation may be attributable to decreased inflammatory signaling within adipocytes
or adipose tissue macrophages. These observations have
provided great insight into the central role of adipose tissue
toward the metabolic syndrome. At the same time, recent
clinical trials have unexpectedly found that intervening in
such a complex and central physiologic process without
comprehensive understanding can carry unexpected and potentially devastating risks. These discoveries also beg the
question of whether anti-inflammatory therapies directed
specifically toward the adipocyte offer an effective and safe
approach to prevent CVD.
Acknowledgments
The authors were supported by an American Diabetes Association
Medical Scientist Training grant (A.H.B.), National Institutes of
Health grant R01-DK55758 (P.E.S.), and a grant from the Yamanouchi USA Foundation. P.E.S. is also a recipient of an Irma T.
Hirschl career scientist award. We would like to thank Dr Andrea
Nawrocki for helpful comments on this manuscript.
References
1. Lowe G. The relationship between infection, inflammation, and cardiovascular disease: an overview. Ann Periodontol. 2001;6:1 8.
2. Fearnley GR, Chakrabarti R, Avis PR. Blood fibrinolytic activity in
diabetes mellitus and its bearing on ischaemic heart disease and obesity.
BMJ. 1963;5335:921923.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
947
insulin resistance and glucose intolerance of aging: an adipokinemediated process? Diabetes. 2002;51:29512958.
Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E,
Roka R, Schernthaner G. Impact of weight loss on inflammatory
proteins and their association with the insulin resistance syndrome in
morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003;23:
10421047.
Kao AH, Sabatine JM, Manzi S. Update on vascular disease in systemic
lupus erythematosus. Curr Opin Rheumatol. 2003;15:519 527.
Rupprecht HJ, Blankenberg S, Bickel C, Rippin G, Hafner G, Prellwitz
W, Schlumberger W, Meyer J. Impact of viral and bacterial infectious
burden on long-term prognosis in patients with coronary artery disease.
Circulation. 2001;104:2531.
Espinola-Klein C, Rupprecht H, Blankenberg S, Bickel C, Kopp H,
Victor A, Hafner G, Prellwitz W, Schlumberger W, Meyer J. Impact of
infectious burden on progression of carotid atherosclerosis. Stroke.
2002;33:25812586.
Deliargyris EN, Madianos PN, Kadoma W, Marron I, Smith SC Jr, Beck
JD, Offenbacher S. Periodontal disease in patients with acute myocardial
infarction: prevalence and contribution to elevated C-reactive protein
levels. Am Heart J. 2004;147:10051009.
Sowers J. Obesity as a cardiovascular risk factor. Am J Med. 2003;115:
37S 41S.
Kroop IG, Shackman NH. Level of C-reactive protein as a measure of
acute myocardial infarction. Proc Soc Exp Biol Med. 1954;86:9597.
Anzai T, Yoshikawa T, Shiraki H, Asakura Y, Akaishi M, Mitamura H,
Ogawa S. C-reactive protein as a predictor of infarct expansion and
cardiac rupture after a first Q-wave acute myocardial infarction. Circulation. 1997;96:778 784.
Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T,
Benjamin EJ, Sawyer DB, Levy D, Wilson PW, DAgostino RB; Framingham Heart Study. Inflammatory markers and risk of heart failure in
elderly subjects without prior myocardial infarction: the Framingham
Heart Study. Circulation. 2003;107:1486 1491.
Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor.
Circulation. 2004;109:II2II10.
Saito M, Ishimitsu T, Minami J, Ono H, Ohrui M, Matsuoka H.
Relations of plasma high-sensitivity C-reactive protein to traditional
cardiovascular risk factors. Atherosclerosis. 2003;167:7379.
Ridker P. Clinical application of C-reactive protein for cardiovascular
disease detection and prevention. Circulation. 2003;107:363369.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive
protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
J Am Med Assoc. 2001;286:327334.
Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. Weight loss
reduces C-reactive protein levels in obese postmenopausal women. Circulation. 2002;105:564 569.
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. J Am Med
Assoc. 2003;289:1799 1804.
Paul A, Ko KW, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L.
C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004;109:647 655.
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.
Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T,
Pepys MB. C-reactive protein and complement are important mediators
of tissue damage in acute myocardial infarction. J Exp Med. 1999;190:
17331740.
Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of
C-reactive protein on human endothelial cells. Circulation. 2000;102:
21652168.
Verma S, Wang CH, Weisel RD, Badiwala MV, Li SH, Fedak PW, Li
RK, Mickle DA. Hyperglycemia potentiates the proatherogenic effects
of C-reactive protein: reversal with rosiglitazone. J Mol Cell Cardiol.
2003;35:417 419.
Labarrere CA, Zaloga GP. C-reactive protein: from innocent bystander
to pivotal mediator of atherosclerosis. Am J Med. 2004;117:499 507.
Nickenig G, Harrison DG. The AT(1)-type angiotensin receptor in
oxidative stress and atherogenesis: part II: AT(1) receptor regulation.
Circulation. 2002;105:530 536.
948
Circulation Research
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
949
113. Wang TD, Chen WJ, Lin JW, Chen MF, Lee YT. Effects of rosiglitazone on endothelial function, C-reactive protein, and components of
the metabolic syndrome in nondiabetic patients with the metabolic
syndrome. Am J Cardiol. 2004;93:362365.
114. Moller DE, Berger JP. Role of PPARs in the regulation of obesityrelated insulin sensitivity and inflammation. Int J Obes Relat Metab
Disord. 2003;27:S17S21.
115. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen
JK, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia.
Safety of treatment, changes in risk factors, and incidence of coronary heart
disease. N Engl J Med. 1987;317:12371245.
116. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M,
Heinonen OP, Frick MH. 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.
Circulation. 1992;85:37 45.
117. Delerive P, Martin-Nizard F, Chinetti G. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator
protein-1 signaling pathway. Circ Res. 1999;85:394 340.
118. Madej A, Okopien B, Kowalski J, Zielinski M, Wysocki J, Szygula B,
Kalina Z, Herman ZS. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia
IIb. Int J Clin Pharmacol Ther. 1998;36:345349.
119. Staels B, Koenig W, Habib A. Activation of human aortic smoothmuscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998;393:790 793.
120. Di Napoli M, Papa F. Angiotensin-converting enzyme inhibitor use is
associated with reduced plasma concentration of C-reactive protein in
patients with first-ever ischemic stroke. Stroke. 2003;34:29222929.
121. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003;35:881900.
122. Niklason A, Hedner T, Niskanen L, Lanke J. Development of diabetes is
retarded by ACE inhibition in hypertensive patientsa subanalysis of the Captopril Prevention Project (CAPPP). J Hypertens. 2004;22:645652.
123. Kinlay S, Schwartz GG, Olsson AG, Rifai N, Leslie SJ, Sasiela WJ, Szarek
M, Libby P, Ganz P; Myocardial Ischemia Reduction With Aggressive
Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances
the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108:15601566.
124. Kinlay S, Selwyn AP. Effects of statins on inflammation in patients with
acute and chronic coronary syndromes. Am J Cardiol. 2003;91:9B13B.
125. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA
reductase inhibitors: statins as antiinflammatory agents? Circulation.
2004;109:II18 II26.
126. van Harmelen V, Skurk T, Rohrig K, Hauner H. HMG-CoA reductase
inhibitor cerivastatin inhibits interleukin-6 expression and secretion in
human adipocytes. Horm Metab Res. 2003;35:466 470.
127. 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;110:36873692.
128. Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A. Circulating
adiponectin and resistin levels in relation to metabolic factors, inflammatory
markers, and vascular reactivity in diabetic patients and subjects at risk for
diabetes. Diabetes Care. 2004;27:24502457.
129. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP,
Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE,
Olefsky JM, Buchanan TA, Scherer PE. Complex distribution, not absolute
amount of adiponectin, correlates with thiazolidinedione-mediated
improvement in insulin sensitivity. J Biol Chem. 2004;279:1215212162.
130. Woodward M, Lowe GD, Francis LM, Rumley A, Cobbe SM. A randomized comparison of the effects of aspirin and clopidogrel on
thrombotic risk factors and C-reactive protein following myocardial
infarction: the CADET trial. J Thromb Haemost. 2004;2:1934 1940.
131. Monakier D, Mates M, Klutstein MW, Balkin JA, Rudensky B, Meerkin D,
Tzivoni D. Rofecoxib, a COX-2 inhibitor, lowers C-reactive protein and in-6
levels in patients with acute coronary syndromes. Chest. 2004;125:16101615.
132. Tendera M, Wojakowski W. Role of antiplatelet drugs in the prevention
of cardiovascular events. Thromb Res. 2003;110:355359.
133. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H,
Avorn J. Relationship between selective cyclooxygenase-2 inhibitors
and acute myocardial infarction in older adults. Circulation. 2004;109:
2068 2073.