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Adipose Tissue, Inflammation, and Cardiovascular Disease

Anders H. Berg and Philipp E. Scherer


Circ Res. 2005;96:939-949
doi: 10.1161/01.RES.0000163635.62927.34
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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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

Philipp E. Scherer, Guest Editor

Adipose Tissue, Inflammation, and Cardiovascular Disease


Anders H. Berg, Philipp E. Scherer
AbstractMounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that
contributes to obesity-associated vasculopathy and cardiovascular risk. Circulating mediators of inflammation
participate in the mechanisms of vascular insult and atheromatous change, and many of these inflammatory proteins are
secreted directly from adipocytes and adipose tissue derived macrophages. Several factors linking obesity with an
increased cardiovascular risk have been identified. The adipocyte-specific secretory protein adiponectin is a particularly
promising candidate in this context. Its levels are decreased in obesity. Adiponectin may mediate some of its
demonstrated cardioprotective effects through its anti-inflammatory properties. In addition to decreased expression of
beneficial adipokines, secretion of a host of inflammatory factors from visceral adipose tissue may contribute to the
increased cardiovascular risk associated with obesity. The cardioprotective effects of many of the most popular drug
regimens corroborate these conclusions, demonstrating that along with improvements in other therapeutic end points,
they mediate improvements in systemic inflammation. In some cases, these improvements are attributable to direct
suppression of inflammatory signaling in adipocytes. The targeted suppression of various proinflammatory cascades in
adipocytes specifically represents an exciting new therapeutic opportunity for the cardiovascular disease area. (Circ Res.
2005;96:939-949.)
Key Words: adipocyte secretion inflammation

he Greek physician Hippocrates observed that Sudden


death is more common in those who are naturally fat than
in the lean, in 400 BC. For many centuries, this astute
observation went completely unexplained. Hypercholesterolemia was, for many years, the predominating pathogenic
theory of atherosclerosis. Although some aspects of this
model still hold, we now know that the connections between
obesity, fatty arteries, and a vulnerable heart are far more
complicated and that inflammation plays a major part in
disease progression. Cardiovascular disease (CVD) is associated with elevated markers of systemic inflammation, includ-

ing C-reactive protein (CRP) and members of the coagulation


cascades.1 Elevated levels of these proteins were also associated with infarction risk factors, such as obesity, diabetes
mellitus, and angina pectoris.2 Despite these intriguing associations, the increase in systemic inflammation was generally
thought to be a result of local atheromatous inflammation.
The pathogenic significance of systemic inflammation was
mostly eclipsed by the vigorous advances in lipid research.
Subsequent studies have demonstrated the importance of
systemic inflammation and demonstrated that this systemic
inflammation is not merely a reactive sequelae of atherogen-

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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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.

Adipose Tissue Is a Mediator of Inflammation


and Innate Immunity
A total of 99% of the worlds metazoan species rely solely on
innate immunity to defend themselves from infection. For
insects, an organ called the fat body mostly mediates this
response. The fat body has a receptor for bacterial and fungal
cell wall constituents called the Toll receptor. This receptor
activates the nuclear factor B (NF-B) signaling cascade
and induces the secretion of antibacterial peptides and other
defense mechanisms. The insect fat body simultaneously
manages the animals liver functions and the storage of
lipids.3 At some point during evolution, vertebrates split these
metabolic duties between the liver and adipose tissue. But
what happened to the functions of innate immunity? Since the
discovery of innate immunity and the acute phase response in
humans, it has been thought that these functions were
primarily the domain of the liver,4 but more recent evidence
shows that when fat storage was delegated to adipose tissue,
the ability to fulfill some aspects of innate immunity was
preserved in adipose tissue as well.
In addition to adipocytes, adipose tissue contains fibroblasts, preadipocytes, tissue resident macrophages, and vascular constituents. Macrophages are known to be crucial
contributors to inflammation, but more recently, it has been
recognized that adipocytes demonstrate significant intrinsic
inflammatory properties as well. Like macrophages, the
adipocyte is exquisitely sensitive to infectious disease agents
and cytokine-mediated inflammatory signals; it expresses a
host of receptors, enabling it to sense the presence of
pathogens and inflammation, and on stimulation of these
receptors, it activates multiple inflammatory signal transduction cascades, and induces and secretes a number of potent
inflammatory cytokines and acute phase reactants. Adipocytes are sensitive to the effects of tumor necrosis factor-
(TNF-), which, through its p55 and p75 TNF receptors,
stimulates NF-B, extracellular signal-regulated kinase, and
p38 mitogen-activated protein kinases PI-3 kinase and junN-terminal kinase cascades.5 The mammalian toll-like lipopolysaccharide (LPS) receptor TLR4 is expressed in tissue
and in vitro cultured adipocytes. When stimulated with

endotoxin, these receptors activate p65/p50 and p68/p52


NF-B signal transduction pathways.6 In turn, these pathways
induce the expression of inflammatory mediators such as
interleukin-6 (IL-6), TNF-, and serum amyloid A3 (SAA3).
At the same time, endotoxin further sensitizes the adipocyte
to infectious pathogens, inducing expression of the toll-like
receptor for fungal wall components (TLR2). It has been
demonstrated that adipocytes are responsive to IL-1, IL-4,
IL-6, IL-11, interferon- (IFN-), and fungal cell wall components, with a downstream activation of inflammatory
signaling cascades.7,8 These inflammatory signaling pathways are differentially regulated during adipogenesis; adipocyte differentiation entails a dramatic induction of expression
of NF-B subunits p65, p68, p52, and the inhibitor of NF-B
(IB), as well as changes in NF-B constitutive nuclear
localization/promoter binding, constitutive IL-6 secretion,
and modulation of LPS responsiveness.6 The induction of p52
and p68, their constitutive nuclear localization and increased
activity, and a decrease in LPS-inducible p65/p50 activity
after differentiation is reminiscent of activated dendritic cells,
suggesting a similar immunomodulatory switch and inflammatory function for these 2 cell types.9
In response to infectious and inflammatory signals, adipocytes have been shown to induce expression and secretion of
several acute phase reactants and mediators of inflammation,
including TNF-, plasminogen activator inhibitor-1 (PAI-1),
IL-1, IL-6, IL-8, IL-10, and IL-15, leukemia inhibitory
factor, hepatocyte growth factor, SAA3, macrophage migration inhibitory factor, haptoglobin, complement factors B, D,
C3, prostaglandin E2, and potential inflammatory modulators
such as leptin, adiponectin, and resistin.10 Although many of
these activities are restricted to autocrine and paracrine
effects, some of these cytokines secreted from adipocytes and
adipose-resident macrophages make significant contributions
to systemic inflammation.

Obesity Is Associated With Increased Local


Adipose Inflammation
Discovery of the contribution of adipose tissue toward inflammation during acute infections prompted the question as
to whether this physiological response to infection may also
be dysregulated in obesity. In 1993, it was discovered that
TNF- expression was upregulated in adipose tissue of obese
mice.11 The induction of inflammatory mRNA transcripts in
adipose tissue can originate in either adipocytes or their
surrounding resident macrophages, and adipocytes and resident macrophages not only contribute independently to the
local adipose inflammatory output, they each synergistically
stimulate inflammatory activity of the other. Heterotypic
signaling experiments using cultured adipocyte conditioned
media have demonstrated that the inflammatory signals secreted by unstimulated adipocytes induce a dramatic increase
of IL-6 and TNF- secretion by otherwise unstimulated
cultured macrophages in vitro.6 This autocrine and paracrine
signaling becomes particularly pronounced in obese states.
Although adipose is usually populated with only 5% to 10%
macrophages, diet-induced weight gain causes a significant
macrophage infiltration, with macrophages constituting up to
60% of all cells found in adipose tissue.12 The close working

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Berg and Scherer


relationship between the adipocyte and the macrophage is
also reflected in the transcriptional program of obese adipose
tissue cells. In mice fed a high-fat diet, weight gain is
associated with induction of many adipose tissue inflammatory pathways: as many as 59% of the total adipose tissue
mRNA transcripts induced during diet-induced weight gain
are inflammation-related genes.13 In addition to induced
mRNA levels, protein secretion of IL-6, TNF-, PAI-1,
angiotensinogen, complement factor C3, tissue factor, and
other inflammatory cytokines is elevated in adipose explants
from obese patients.14,15
Adipose tissue is not usually thought of as an immune or
inflammatory organ. However, the discovery of elevated
secretion of these factors from obese adipose tissue provided
the first evidence of a direct connection between obesity and
systemic inflammation.

Obesity Is Associated With Increased


Systemic Inflammation
A growing body of evidence demonstrates that increased
adipose tissue mass contributes directly toward an increase in
systemic inflammation. The earliest indications of this phenomenon were reported in 1985, when an article noted
positive correlations between body mass and peripheral
leukocyte counts.16 Since then, a large number of studies have
found that increased body mass index (BMI) correlates with
increases in systemic circulating levels of inflammatory
proteins such as CRP, IL-6, PAI-1, P-selectin, vascular cell
adhesion molecule 1 (VCAM-1), fibrinogen, angiotensinogen, SAA3, and 1-acid glycoprotein. Considering that
adipose and adipocytes produce all of these factors, it can be
inferred that adipose itself is a large contributor to these
systemic increases.8,17
The systemic inflammation observed in obesity is undoubtedly derived not only from adipose tissue but also from the
liver and other important inflammatory tissues. The relative
contributions of each tissue vary a great deal. For example,
SAA3 is upregulated in adipose tissue but not in the liver of
obese mice. Although 1-acid glycoprotein is expressed in
adipose tissue, it is upregulated primarily in the liver under
conditions of increased obesity. However, even for some of
the proteins derived from the liver, it is believed that adipose
tissue is the initial driving force for upregulation. One of the
best examples of this is the clinical marker of systemic
inflammation CRP. The regulation of this protein in the liver
is believed to be driven by IL-6. It may be IL-6 derived from
visceral adipose tissue draining directly into the portal system
that causes the obesity-associated rise of liver CRP production.4,18 Furthermore, in addition to liver-derived CRP, newer
data show that adipose tissue itself may contribute to obesityassociated increased CRP levels.19 Although the direct contributions of adipose tissue toward systemic CRP levels may
be limited, it is clear that adipocyte- and adipose tissue
stroma derived factors have a strong impact on the production of CRP in other tissues.

Adipocytes and Cardiovascular Disease

941

studies. Whether the weight loss is attributable to decreased


dietary intake, increased fuel use through exercise, liposuction, or bariatric surgery, loss of adipose tissue is associated
with a decrease in markers of inflammation. Weight loss
achieved through dietary intervention alone or diet and
exercise resulted in decreased circulating IL-6, CRP, PAI-1,
TNF-, soluble TNF receptor, P-selectin, intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and IL-18 in men and
women of various age groups and BMIs.20,21
Weight loss by liposuction in obese patients was associated
with significant decreases in circulating CRP, IL-6, IL-18,
and TNF and sustained (6 months postoperative) improvements in insulin resistance.22 In contrast, Klein et al reported
recently that large-volume subcutaneous abdominal liposuction did not significantly alter plasma concentrations of CRP,
IL-6, TNF-, and adiponectin, and did not significantly affect
other risk factors for coronary heart disease and insulin
sensitivity.23 The main lesson from this latter study is that
liposuction of subcutaneous fat pads may not have as strong
an impact as surgical removal of visceral adipose tissue.24
In another form of dietary weight loss, gastric bypass
surgery resulted in improved insulin sensitivity, amelioration
of diabetes, and significant decreases in circulating IL-6 and
CRP levels 14 months after the procedure.25 Not only do
these findings strengthen the evidence for the direct contribution of obese adipose tissue to systemic inflammation, they
also imply that many of the health benefits of weight loss are
attributable to these decreases in inflammatory signals.

Systemic Inflammation Is Associated With


Increased Cardiovascular Risk
Systemic inflammation has been reported to be present before
any evidence of myocardial infarction. This was first interpreted as an inflammatory response to the developing atheromatous vascular damage. However, an alternative explanation could be offered by suggesting that systemic
inflammation is causing atherosclerosis rather than being the
result of it. This interpretation is supported by the observation
that patients with pre-existing inflammatory diseases have a
dramatically increased risk of CVD at younger ages. Patients
with autoimmune diseases such as rheumatoid arthritis and
lupus have accelerated rates of atherosclerosis.26 Systemic
inflammation resulting from untreated indolent infections like
periodontal disease is also correlated with increased cardiovascular risk.27 One of these studies found that serological
evidence of past or ongoing chlamydial infection had increased amounts of carotid arteriosclerosis and demonstrated
that empiric antichlamydial antibiotic treatment in these
patients actually slowed their carotid arteriosclerotic narrowing over the next 3 years compared with untreated controls.28
Because there was no evidence of direct infectious infiltration of these patients atheromatous lesions, these studies
made conclusions similar to the studies on rheumatoid arthritis (ie, that systemic inflammation, per se, was mediating
these vasculopathic effects).29

Weight Loss Decreases Systemic Inflammation

Mechanisms of Cardiovascular Pathology by


Systemic Inflammation

Evidence for a connection between obesity and inflammation


has also been found in the context of clinical weight loss

Obesity contributes to CVD via all of the proven mechanisms


of coronary vasculopathy: atherosclerosis, hypercholesterolemia,

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hypercoagulability, platelet dysfunction, insulin resistance and type


2 diabetes, and the metabolic syndrome.30 In turn, these many
contributors are linked into a web of reciprocal comorbidities, with
circulating serum factors mediating the connections between these
disease states. Most of these circulating mediators are participants in
systemic inflammation. Thus, the clearest means to describe this
web is by dissecting our understanding of these circulating factors
and discuss the quality of the evidence for their connections to
obesity and cardiovascular pathology. Adipose tissue is a major
source for many of these factors, or it exerts direct control over
expression of these factors in other tissues.

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

is in vitro evidence demonstrating that it also may be an active


mediator of inflammatory vasculopathy. After myocardial infarction, CRP accumulates within damaged myocardium, and it
is thought to participate in the opsonization of necrotic tissue.42
Because of the correlation between circulating CRP levels and
postinfarction prognosis, it was proposed that the complementactivating and opsonizing activities of CRP actually participate
in the postinfarction pathology.18,42 However, even before infarction, circulating CRP has atherogenic activities on vascular
endothelium and smooth muscle. Elevated CRP levels have been
associated with endothelial dysfunction in the form of inappropriate vascular constriction/relaxation. CRP has been shown to
cause induction of endothelial adhesion proteins ICAM-1,
VCAM-1, E-selectin, P-selectin, and angiotensin type 1 receptor.43,44 Additionally, CRP has been implicated in the activation
of endothelial NF-B, induction of endothelial IL-1, PAI-1,
IL-6, TNF-, monocyte chemoattractant protein-1 (MCP-1),
endothelin-1, and tissue factor, and inhibition of endothelial NO
synthase and NO signaling.45 Furthermore, many of these factors
regulate CRP levels reciprocally; thus, even in the absence of
tissue damage, CRP seems to be an amplifier of vascular
inflammation. Increased expression of these adhesion proteins
and cytokines results in increases in leukocyte adherence,
chemotaxis, and extravasation into the inflamed subendothelial
intima, with cellular inflammation and eventual foam cell
accumulation. They also induce loss of endothelial and smooth
muscle NO generation and proper vascular relaxation. Combined with increased vascular contractile signals by endothelin-1
and angiotensin II (AT-II), this results in inappropriate vascular
contraction/relaxation and contributes to hypertension. Other
effects include increased smooth muscle cell migration, proliferation, and vascular remodeling.46 Finally, the abovementioned effects on NO and induction of endothelin-1 and
P-selectin have proaggregating effects on platelets.47 These
multiple molecular mechanisms for vasculopathic effects by
CRP may explain the central position of CRP within the context
of cardiovascular risk factors.

Plasminogen Activator Inhibitor-1


PAI-1 is a regulatory protein of the coagulation cascade, which
is elevated in inflammatory and obese states as well as in the
metabolic syndrome; and although it usually is primarily derived
from platelets and endothelium, there is evidence to show that
much of the elevation in obesity is attributable to upregulated
production by adipose tissue itself.48,49 Obesity is also associated
with increased circulating levels of the procoagulant factors
tissue factor, fibrinogen, von Willebrand factor, and factor VII.
Many of the circulating cytokines elevated in obese states also
cause endothelial activation, resulting in low levels of platelet
activation, prostaglandin secretion, and plug formation.50 Thus,
when obesity-induced increases in clotting factor levels and
platelet activation are combined with the decreased rate of
fibrinolysis attributable to increased PAI-1, they represent a
hypercoagulable state, which is thought to contribute to atherogenesis via increased deposition of platelets and fibrinous
products to developing plaques. This hypothesis has been
validated by the demonstration that elevated levels of each of
these prothrombotic serum factors are associated with increased
cardiovascular risks.51

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Berg and Scherer

Tumor Necrosis Factor-

The contribution of TNF- to vasculopathy is complex and


controversial. Obesity-associated TNF- is primarily secreted
from macrophages accumulated in obese adipose tissue,
whereas the adipocytes, per se, predominantly produce unsecreted, membrane-bound TNF-.12,52 The secreted adipose
tissue TNF- is specifically increased in visceral adipose
depots.53 The resulting systemic rise in circulating TNF- has
been implicated in causing adipocyte insulin resistance.54,55
Thus, some of the contribution of TNF- to vasculopathic
processes may be mostly through its involvement in the
development of insulin-resistant diabetes and the ensuing
hyperglycemia.56 Circulating TNF- may also contribute by
its induction of CRP production and general systemic inflammation, which, in turn, impacts on the vasculature. In vitro
experiments have also shown that TNF- increases activation
of endothelial and smooth muscle NF-B, which, in turn,
induces vascular adhesion molecules and cytokines, resulting
in inflammatory and foam cell accumulation.57
Despite these intriguing in vitro data, the animal studies on
TNF- and development of atherosclerosis have produced
mixed results. Although reducing TNF- levels in apoEdeficient mice resulted in significant decrease of atheromatous
lesions,58 in a wild-type background, it produced no improvements.59 Rats treated with antiTNF- therapy showed no
improvement in their rate of postbypass graft arteriosclerosis.60
In fact, mice deficient for the p55 TNF- receptor exhibited
accelerated atherosclerosis.61 Finally, although TNF- is thought
to play a role in the progression of ischemia-related congestive
heart failure, anti-TNF therapy has shown no benefits for
congestive heart failure progression in patients.62 Despite these
conflicting results, there remains a great interest in testing
antiTNF- therapies for cardioprotective effects.

Interleukin-6

Like TNF-, the data as to the significance of increased systemic


IL-6 levels in obese states are mixed and controversial. Obesityassociated induction of adipose IL-6 production induces CRP
secretion, and there are data that suggest IL-6 decreases lipoprotein lipase activity, which results in increased macrophage
uptake of lipids. In young atheromatous lesions, macrophage
foam cells and smooth muscle cells express IL-6, suggesting a
role for this cytokine in the earliest stages of atherosclerosis.
Furthermore, circulating IL-6 stimulates the hypothalamicpituitary-adrenal axis, activation of which is associated with
central obesity, hypertension, and insulin resistance.18
Despite the association of increased IL-6 levels with vasculopathic disease states, and data demonstrating possible specific
provasculopathic activities by IL-6, there is growing evidence
that it also has roles in inducing lipolysis and decreasing appetite
and weight gain, thus controlling obesity-associated pathology.63,64 The current understanding of the roles of IL-6 and
TNF- in the context of obesity and vascular pathology is
ambiguous. Although these cytokines may play an important
role in the beneficial control of metabolic functions in lean,
physically active individuals,65 their overall effects on vasculopathy in obese states is still unknown. It remains highly likely
that they contribute to obesity-associated systemic inflammation
and its sequelae and remain potentially important targets for

Adipocytes and Cardiovascular Disease

943

prevention of inflammation-induced insulin resistance or


vasculopathy.

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

Vascular Endothelial Growth Factor


Along with increased AT-II, obesity is associated with
increased levels of the angiogenic factor vascular endothelial
growth factor (VEGF), which has been demonstrated to play
a part in hypertension and atherogenesis. In adults, most
organ systems have reached their final size and are programmed to be maintained at steady state. However, adipose
tissue is unique because of its almost unlimited growth
potential. Therefore, it is not surprising that upon differentiation, adipocytes begin to express angiogenic growth factors
like VEGF,71 which can increase the vascular bed for the
expanding needs of adipose tissue. Elevated insulin levels are
an additional signal of caloric excess and continued adipose
expansion, and correspondingly, it has been shown that
adipocytes express and secrete VEGF in an insulin-dependent
manner,72 leading to the observation that obese states are
associated with increased adipose tissue VEGF secretion.
Furthermore, given the regulation of endothelial VEGF secretion by AT-II and the elevated AT-II levels in obese states,
it is easy to see why obesity should be associated with
increased systemic VEGF levels.73 Like many of the inflammatory cytokines we reviewed here, VEGF levels are particularly elevated in the context of visceral adipose tissue
expansion,10,73 underlining the significance of visceral adipose tissue and VEGF for hypertension, the metabolic syndrome, and vasculopathy (discussed below). Although the
angiogenic effects of VEGF are necessary for proper vascular
remodeling after angioplasty and for the genesis of collaterals
in diabetic peripheral vascular disease, VEGF is also implicated in the initial development of atheromatous change and
postcatheterization restenosis.74 Recent data indicate that in
addition to its effects on vascular remodeling, the angiogenic
growth factor VEGF plays a role in AT-IIinduced vascular
inflammation and remodeling, specifically increasing aortic
subendothelial macrophage accumulation and intimal thickening.75 As illustrated in the results of anti-VEGF treatment

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in postcatheterization coronary restenosis, VEGF has already


been demonstrated to be an important target in specific
cardiac vasculopathies. It remains to be seen just how
important the obesity-induced changes in systemic VEGF are
and what the role of anti-VEGF therapies may be in the
context of obesity and cardiovascular risk states.

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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Berg and Scherer


trophic signals via AMPK.96 Thus, the decreased levels of this
one protein in obesity represent two (if not more) connections to
cardiac risk: inflammation-induced cardiovascular insufficiency
and direct myocardial insult.

Association Between Visceral Adipose Mass,


Secretion of Inflammatory Cytokines, Insulin
Resistance, and the Metabolic Syndrome
A growing body of literature demonstrates that body fat
distribution, not the absolute amount of adipose tissue, is
what leads to the increased risks for CVD observed in many
overweight individuals,97 pinpointing the intra-abdominal
visceral fat pads as the major culprits in the process. These
observations are best typified by the data regarding the
metabolic syndrome.98 The American Heart Association defines the metabolic syndrome as the combination of abdominal obesity, dyslipidemia, hypertension, and insulin resistance, 99 a constellation of disorders that bestow a
cardiovascular risk far greater than any of its individual
components.100 The defining characteristic of this disease is
increased visceral adipose tissue mass, but since its description, it has been a mystery exactly how the other defects relate
to this fat deposition pattern. More recently, it has been
discovered that the second defining characteristic of the
metabolic syndrome is increased systemic inflammation. In
fact, the association between CRP and the metabolic syndrome is so strong it has been suggested that it become
another diagnostic requirement.101 What role does visceral
adipose tissue play in obesity-associated inflammation? And
what is the impact of these two players on development of the
insulin resistance, hypertension, and dyslipidemia that define
the remainder of the syndrome? Visceral fat explants have
been shown to secrete far greater amounts of CRP, IL-6,
TNF-, VEGF, angiotensinogen, and PAI-1 compared with
dissected subcutaneous adipose.10,15,102 Products released
from visceral adipose tissue travel directly to the liver via the
portal vein. Thus, the livers of obese subjects are directly
downstream of the visceral fat pads that show a dramatic
upregulation of inflammatory cytokines. When compared
with BMI-matched controls with increased subcutaneous fat
deposition, patients with increased amounts of abdominal fat
have increased circulating levels of CRP, TNF-, IL-6, PAI-1,
angiotensinogen, increased platelet-activating eicosanoids, and
increased numbers of activated platelets.15,50,53,102,103
Not surprisingly, when a number of studies that originally
focused on overall obesity were re-evaluated specifically for
the effects of central obesity, a dramatic and previously
unnoticed association between intra-abdominal fat accumulation, its resulting inflammatory signals, and the other
correlates of the metabolic syndrome emerged. Compared
with BMI-matched controls, obese patients with visceral
adiposity display particularly recalcitrant insulin resistance,
dyslipidemia, hypercoagulability with increased thrombotic
risks, and increased hypertension.104 106 Instead of indicting
all types of overweight, it may be better presented that
obesity, per se, is simply a risk factor for the development of
central obesity, and it is central obesity that directly underlies
insulin resistance and subclinical inflammation, which, in
turn, leads to the metabolic syndrome and CVD.

Adipocytes and Cardiovascular Disease

945

Effects of Cardioprotective Therapies on


Systemic Inflammation
In addition to the epidemiological evidence reviewed above
for the role of inflammation in obesity-associated cardiac and
cardiovascular risk, clinical studies of patients on cardioprotective drug regimens have revealed that many of the
pharmacotherapies mediate their benefits, at least in part,
through adipose-specific anti-inflammatory activities. This is
the case most strikingly for one class of drugs that improves
adipose tissue physiology and insulin sensitivity, the peroxisome proliferator-activated receptor- (PPAR) agonists
(thiazolidinediones). PPAR agonists, which primarily act on
adipocytes through their defining transcription factor target
PPAR, not only increase peripheral and liver insulin sensitivity but also cause dramatic decreases in indicators of
systemic inflammation. In obese diabetic patients, rosiglitazone has been shown to decrease circulating CRP,107,108 IL-6,
matrix metalloproteinase-9 (MMP-9) activity, white blood
cell count, and platelet activation,41,107109 effects that are
independent of improvements in insulin sensitivity.107 In
patients with angiographic evidence of coronary artery disease, glitazone drugs decrease circulating levels of E-selectin,
von Willebrand factor, CRP, fibrinogen, TNF-, and PAI-1,
and inhibit progression of intimal thickening.110 Finally, in
patients with hypertension or nondiabetic metabolic syndrome, glitazones have been shown to decrease CRP, TNF-,
fibrinogen, and PAI-1.111113 Glitazones are thought to mediate their antidiabetic and anti-inflammatory effects via actions on the PPAR transcription factor expressed in adipocytes and macrophages. The anti-inflammatory effects of
glitazones are felt to be mediated partly by their beneficial
effects on dyslipidemia, but there is also evidence that
glitazones may directly modulate inflammation via transcription factors such as NF-B.114
Similar to their -agonist cousins, PPAR agonists, like
the fibrates, have also demonstrated anti-inflammatory properties in addition to their other beneficial effects on metabolism. Fibrates are used to treat hyperlipidemias because of
their effects on the liver, and the cardioprotective effects of
these compounds in obese patients have been attributed to
this aspect of their bioactivity.115,116 However, more recently,
it was shown that fibrates lower circulating systemic inflammatory mediators such as endothelin-1, IL-6, CRP, TNF-,
and IFN-.117,118 Their effects may be mediated through
activities on inflammatory signal transduction proteins cyclooxygenase-2 (COX-2), NF-B, and activator protein-1.119
The proinflammatory effects of AT-II were briefly reviewed above, and thus, it is not surprising that the antihypertensive ACE inhibitors and AT-II receptor blockers also
have significant anti-inflammatory effects in patients with
high cardiovascular risk. In hypertensive patients with and
without demonstrable CVD, ACE inhibitors and angiotensin
receptor blockers caused dramatic decreases in CRP, IL-6,
MMP-9, and platelet aggregation.69,120 As mentioned earlier,
the proposed mechanisms for the anti-inflammatory effects of
either drug involve blockade of the effects of angiotensin on
vascular permeability, regulation of adhesion molecules and
chemokines, and direct activation of invading inflammatory
cells.121 Clinical trials with hypertensive patients also re-

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May 13, 2005

vealed surprising antidiabetic properties. In hypertensive


diabetic patients, AT-II blockade improved patients glycemic control and reduced the relative risk of developing
diabetes in the nondiabetic patients,122 and these changes
were also associated with decreases in systemic inflammation.104 Perhaps the most intriguing implication of these
clinical trials was that AT-IImediated increases in vascular
and systemic inflammation may mediate part of the progression from mere insulin resistance to overt hyperglycemia, and
thus, they indirectly recruited yet another powerful vasculopathic mechanism.
In addition to the beneficial effects of antidiabetic and
antihypertensive drugs on the subclinical inflammation, the
hypolipidemic statins have also demonstrated antiinflammatory properties. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) have been shown to
decrease CRP levels in subjects with high cardiovascular
risks,34 and they accelerated the decline of CRP and SAA3
levels after myocardial infarction.123 It is likely that statins
mediate their anti-inflammatory actions by ameliorating the
proinflammatory effects of atherogenic lipoproteins.124 However, newer data suggest that inhibition of HMG-CoA may
also modulate intracellular inflammatory signaling directly.
In endothelial cells, polymorphonuclear cells, monocytes, and
vascular smooth muscle, numerous in vitro studies have
demonstrated that inhibition of HMG-CoA reductase inhibits
inflammatory signaling via modulation of protein prenylation.125 Decreased protein prenylation has been shown to
modulate activity of Ras, Rho, Rac, and Rab signaling
proteins and through these proteins, has effects on adhesion,
migration, proliferation, apoptosis, matrix degradation, and
coagulation.125 In the context of obesity and adipose tissue
derived inflammation, it was discovered recently that the
statin class of drugs may have direct anti-inflammatory
actions on adipocytes themselves. Treatment of cultured
adipocytes with cerivastatin decreased expression and secretion of IL-6.126 The data by these authors further suggested
that the prenylating intermediate geranylgeranyl pyrophosphate was stimulating NF-B p65 activation, and that the
statin inhibition of this prenylation pathway was responsible
for these anti-inflammatory effects.126 Finally, in addition to
their beneficial effects on cytokine levels, it was shown
recently in clinical trials that statins also marginally raise
circulating levels of serum total adiponectin.127 Other studies
fail to see a significant effect of statins on circulating levels
of adiponectin.128 In light of these conflicting reports, it will
be interesting to see whether future studies find changes in the
distribution of adiponectin complexes, similar to the effects
reported for PPAR agonists.129
With accumulating evidence for active roles of inflammation in atherosclerotic progression, as well as data suggesting
that commonly prescribed therapies mediate cardioprotective
activities through their intended mechanisms as well as via
anti-inflammatory effects, two issues arise. First, how much
of obesity-associated cardiac risk is mediated by the observed
systemic inflammation? Second, how can anti-inflammatory
processes specifically be targeted toward adipose tissue?
Aspirin and COX-2 inhibitors are anti-inflammatory and both
lower CRP levels,130,131 but aspirin dramatically reduces

cardiovascular risk,132 whereas the accumulating data on


COX-2 inhibitors suggest an increase in myocardial infarction risk.133 An explanation for this dichotomy may be their
differential effects on platelets. Aspirin inhibits COX-1 and
COX-2 and platelet-activating thromboxane production,
whereas the COX-2 inhibitors tend to have plateletaggregating and vasoactive activities.133 In addition, aspirin
may exert some of its systemic effects by targeting adipocytes
with its anti-inflammatory properties, whereas there is very
little evidence to suggest a direct effect of COX-2 inhibitors
in adipocytes.

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.

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