M E TAB O LI S M CL I NI CA L A N D EX P ER IM EN T AL 6 2 (2 0 1 3) 1 51 3 –1 5 21

Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Reviews

Adipocytokines in relation to cardiovascular disease

Johan Van de Voorde⁎, Bart Pauwels, Charlotte Boydens, Kelly Decaluwé

Department of Pharmacology, Vascular Research Unit, Ghent University, Belgium

A R T I C LE I N FO AB S T R A C T

Article history: Adipose tissue can be considered as a huge gland producing paracrine and endocrine
Received 17 January 2013 hormones, the adipo(cyto)kines. There is growing evidence that these adipo(cyto)kines may
Accepted 6 June 2013 link obesity to cardiovascular diseases. The excessive adipocyte hypertrophy in obesity
induces hypoxia in adipose tissue. This leads to adiposopathy, the process that converts
Keywords: “healthy” adipose tissue to “sick” adipose tissue. This is accompanied by a change in profile
Adipokines of adipo(cyto)kines released, with less production of the “healthy” adipo(cyto)kines such as
Cardiovascular diseases adiponectin and omentin and more release of the “unhealthy” adipo(cyto)kines, ultimately
Obesity leading to the development of cardiovascular diseases. The present review provides a
Adiposopathy concise and general overview of the actual concepts of the role of adipo(cyto)kines in
endothelial dysfunction, hypertension, atherosclerosis and heart diseases. The knowledge
of these concepts may lead to new tools to improve health in the next generations.
© 2013 Elsevier Inc. All rights reserved.

1. Introduction While a minimal amount of adipose tissue is essential

Adipose tissue functions as an energy stock that fills when the
organism has excess of energy and empties when access to
energy is limited. In addition it functions as a cushion and
insulator of the body [1]. The discovery of leptin first demon-
strated that adipose tissue can also be considered as a huge
gland that produces bioactive molecules acting as paracrine and
endocrine hormones, the so called adipo(cyto)kines. The list of
adipo(cyto)kines continues to grow to hundreds of factors [2,3].
Some of these adipo(cyto)kines like leptin play a role in
homeostasis of body weight by controlling food intake. More
recently it has become clear that many adipo(cyto)kines are
mediators in the “adipo-cardiovascular axis”, the cross talk
between adipose tissues, the heart and the vasculature.
for living, the excess of fat in obesity is detrimental and
associated with a high cardiovascular mortality and morbidity.
Both animal and clinical investigations suggest that inflamma-
tion and dysfunction of adipose tissue in obesity, resulting in
aberrant production of adipo(cyto)kines, are key processes that
link obesity to cardiovascular diseases. It should however be
noted that the relationship between cardiovascular disease and
adiposity is often not straight forward as evidenced by the so
called “obesity paradoxes”, namely the observations that an
increase in body fat mass does not always increase morbidity or
mortality, that a decrease in excessive body fat does not always
improve patient health and that an increase in body fat mass
sometimes reduces morbidity or mortality [4]. In the last decade
many research aimed to better understand the link between

Abbreviations: A-FABP, adipocyte fatty acid binding protein; BMI, body mass index; COX-2, cyclooxygenase-2; eNOS, endothelial NO-
synthase; HIF-1α, hypoxia inducible factor-1 alfa; IL-6, interleukin 6; LDL, low density lipoprotein; PAI-1, plasminogen activator inhibitor-
1; PVADRF, perivascular adipose tissue derived relaxing factor; ROS, reactive oxygen species; TNFα, tumor necrosis factor alfa; VCAM-1,
vascular cell adhesion molecule 1.
⁎ Corresponding author. Department of Pharmacology, Vascular Research Unit, Ghent University, De Pintelaan, 185, Blok B-2nd Floor. 9000
Ghent, Belgium. Tel.: +32 93 32 33 42.
E-mail address: Johan.vandevoorde@ugent.be (J. Van de Voorde).

0026-0495/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.metabol.2013.06.004
1514 M ET AB O LI S M CL I NI CA L A N D EX PE R IM EN T AL 6 2 (2 0 1 3) 1 51 3–1 52 1
adipose tissue and the cardiovascular system. Several recent
reviews have addressed in detail different aspects of this link
[5–12]. The present paper aims to provide a concise and general
overview of the actual concepts, supplemented with the most
relevant recent findings related to the intriguing relation
between adipose tissue and cardiovascular diseases.
2. “Adiposopathy”
During positive caloric balance adipocytes become hypertro-
phied. Excessive hypertrophy causes “adiposopathy”, a path-
ologic adipose tissue that creates adverse paracrine,
endocrine and immune responses which may promote
cardiovascular diseases, either directly or indirectly by
stimulating major cardiovascular risk factors such as type-2
diabetes mellitus, high blood pressure or dyslipidemia [13].
The dysfunction of adipose tissue is a key link between obesity
and cardiovascular disease. Excessive adipocyte hypertrophy
disrupts the normal physiological function of fat-cell organ-
elles, as evidenced by increased levels of markers of intracel-
lular endoplasmic reticulum stress and mitochondrial
dysfunction [14,15].
Increasing evidence suggests that hypoxia plays a crucial
role in the adiposopathy process that converts adipose tissue
from “healthy” to “sick”. In obesity in which the amount of
adipose tissue has grown out of proportion, the rapid fat
accumulation outpaces angiogenesis and the relative lack of
blood flow induces both cellular and adipose tissue hypoxia. As
with other body tissues this contributes to cellular and organ
dysfunction [16] and pro-inflammatory responses, all contrib-
uting to metabolic disease [17]. Cell culture studies using
murine and human adipocytes strongly support the modula-
tory role of hypoxia in the production of several pro-inflam-
matory adipokines [18]. Even modest changes in oxygen levels
induce specific changes in gene expression and metabolism of
human adipocytes [19]. This is important to consider since
most in vitro studies are performed using cells oxygenated with
a gas containing 21% oxygen, which is well above the oxygen
tension prevailing in tissues in which oxygen levels are far
below that in arterial blood. As in obesity, also aging is
associated with altered function, size and number of adipose
cells, with altered distribution of adipose tissues in the body
and with hypoxia in adipose tissue, especially in the visceral
depots [20]. Hypoxia may not only result from decreased blood
flow due to increased adipose cell size or from adipose
remodeling, but also from local inflammation, inducing region-
al changes in blood flow. Hypoxic cells secrete chemokines to
attract macrophages [21]. Local hypoxia in adipose tissue also
increases the levels of HIF-1α in adipocytes. HIF-1α may lead to
upregulation of various inflammatory adipo(cyto)kines such as
IL-6, TNFα and monocyte chemotactic protein-1. Upon secre-
tion into the bloodstream these adipo(cyto)kines damage
systemic microvessels and induce dysfunction of adipose
tissue arterioles, further exaggerating the dysregulation of
adipose tissue microcirculation [22,23]. It has also been reported
that hypoxia modulates the vasorelaxing influence of adhering
perivascular adipose tissue in isolated blood vessels [24–26].
Related to cardiovascular diseases one can distinct
“healthy” (of which adiponectin is best characterized) and
“unhealthy” adipo(cyto)kines. Interestingly, the “healthy”
adiponectin and omentin are decreased in obesity while the
“unhealthy” adipo(cyto)kines such as TNFα, IL-6, PAI-1, A-
FABP, lipocalin-2, chemerin, leptin, visfatin, vaspin, resistin
are upregulated in obesity [6,27]. The good news is that
restricted caloric intake and increased exercise lead to de-
creases in the inflammatory adipo(cyto)kines and increases in
the anti-inflammatory cytokines in obese subjects [28].
The pro-inflammatory factors released from adipose tissue
exert adverse effects on the vasculature by direct and indirect
mechanisms. A number of adipo(cyto)kines induce insulin
resistance and metabolic derangements, which are known
risk factors for cardiovascular diseases. Several adipo(cyto)
kines also induce the recruitment and infiltration of mono-
cytes, lymphocytes and neutrophils into the blood vessel wall
to instigate local inflammation. In addition, many adipo(cyto)
kines impair nitric oxide production in endothelial cells and
thus compromise endothelium-dependent vasodilatation [8].
Although obesity is associated with significant cardiovas-
cular morbidity and mortality, excess body fat is actually a
heterogeneous condition. Individuals with similar BMI may
have distinct metabolic and cardiovascular disease risk [29].
This may be due to variation in body fat distribution and could
explain the recommendation to measure waist circumference
as additional information to determine cardiovascular risk. In
this respect one can differentiate between non-ectopic fat (e.g.
subcutaneous adipose tissue) and ectopic fat, the latter being
defined as the excess adipose tissue in locations not
classically associated with adipose tissue storage (e.g. visceral
adipose tissue, intrahepatic, intramuscular, renal sinus,
pericardial, myocardial and perivascular fat). Different loca-
tions of adipose tissues may express different profiles of
adipo(cyto)kines [30].
It is suggested that in state of positive energy balance, the
excess of free fatty acids is stored initially in non-ectopic
subcutaneous adipose tissue. However, once the maximal
capacity of the subcutaneous adipose tissue is reached,
storage shifts to ectopic sites, including the viscera, heart
and vasculature [31]. Interestingly, it has been shown in
mice that transplantation of subcutaneous adipose tissue,
but not visceral adipose tissue, to an intra-abdominal site
resulted in beneficial effects [32]. This is in line with the
idea that the different body stores of adipose tissue constitute
a variety of mini-endocrine glands with unique proteomic
fingerprints [33].
The growing appreciation of the importance of ectopic fat
depots for cardiovascular risk has led to interest in direct
quantification of the different fat depots in the organism. The
ectopic fat depots may exert their detrimental effect on the
cardiovascular system in a systemic endocrine way (e.g.
visceral adipose tissue) but also in a local paracrine way (e.g.
perivascular and epicardial fat) [7]. It should be noted that
adipose tissue is located in close vicinity of the heart and
blood vessels. Epicardial adipose tissue is located along the
large coronary arteries and on the surface of the myocard. The
intimate contact suggests that dysregulation of adipo(cyto)
kines in obesity and other disease states may have local
pathogenic effects on blood vessels. Both pericardial and
perivascular fat depots are, without any barrier, in direct
contact with the underlying tissue, so that factors from these
 M E TAB O LI S M CL I NI CA L A N D EX P ER IM EN T AL 6 2 (2 0 1 3) 1 51 3 –1 5 21
adipose tissues can immediately modulate the function of the
heart and the vasculature. Perivascular fat can induce both
vasodilatation and vasoconstriction by releasing adipocyte-
derived relaxing and constricting factors [34].
The fact that “adiposopathic adipose tissue” develops in
certain but not all fat depots in the organism might explain in
part the various obesity paradoxes [13]. Asian Indians have an
increased adipocyte size, fewer adipocytes, increased visceral
adiposity, increased circulating free fatty acids, increased
leptin levels, increased pro-inflammatory factors and de-
creased anti-inflammatory factors, all elements leading to
increased risk for cardiovascular disease. Therefore patients
of Asian descent have sometimes obesity-related problems
even without marked overweight [35]. A recent study reported
significant race–ethnic differences in circulating adipokines,
which may be related to racial differences in risk for
cardiovascular diseases [36]. Similarly, adiposopathy helps
explain why, for the same age and weight, men have a higher
rate of cardiovascular disease compared with women. During
positive caloric balance, men often expand lower body fat
through the more pathogenic process of adipocyte hypertro-
phy, whereas women typically undergo the less pathogenic
process of adipocyte hyperplasia. Furthermore, men often
store excessive fat in visceral adipose tissue (“apple”), whereas
women rather in peripheral subcutaneous adipose tissue
(“pear”). With this in mind it is not surprising that liposuction
of subcutaneous adipose tissue does not improve cardiovas-
cular risk factors such as hyperglycemia, high blood pressure
and dyslipidemia [37].
3. Adipocytokines and endothelial dysfunction
Endothelial cells are connected through specialized structures
which provide the primary endothelial barrier function.
Endothelial dysfunction due to breakdown of the barrier
promotes atherogenesis as a result of enhanced permeability
through the endothelial layer, increased adherence of leuko-
cytes, monocytes and macrophages and subendothelial
accumulation of cholesterol-bearing lipoproteins.
Adiponectin reduces TNFα-stimulated expression of endo-
thelial adhesion molecules and monocyte attachment. In
addition, adiponectin attenuates the production of ROS
induced by high glucose, oxidized LDL and palmitate in
endothelial cells. It also stimulates endothelial cell migration
and differentiation into capillary-like structures and prevents
apoptosis of endothelial cells. Adiponectin promotes eNOS
phosphorylation in endothelial cells. Endothelium-dependent
vasodilation is impaired in aorta from adiponectin knockout
mice [38]. Administration of recombinant adiponectin in rats
with dietary obesity increases eNOS activity, NO production
and relaxation of aortic rings to endothelium-dependent
vasodilators [39]. Adiponectin also protects against cerebral
ischemia–reperfusion injury in rats through an eNOS-
dependent mechanism. Moreover, the revascularization in
response to tissue ischemia is promoted by adiponectin
through activation of eNOS and/or COX-2 in endothelial cells.
Hypoadiponectinemia is independently associated with
endothelial dysfunction in diabetic patients [9]. The adiponec-
tin concentration in non-diabetic patients is an independent
1515
predictor of coronary endothelial function as evaluated by the
coronary vascular response to acetylcholine [40].
Omentin promotes activation of nitric oxide synthase and
therefore it promotes endothelium-dependent vasorelaxa-
tion, angiogenesis and prevents pro-inflammatory signaling
in endothelial cells [27,41]. Decreased omentin levels have
been linked to endothelial dysfunction in humans [42].
A-FABP is one of the most abundant proteins in mature
adipocytes. It is secreted in blood [43] and is believed to play a
central role in obesity-related cardiovascular disease, possibly
by potentiating lipids-induced inflammation. Plasma A-FAPB
levels are positively correlated with endothelial dysfunction.
A-FABP may contribute to endothelial dysfunction by poten-
tiating lipids-induced impairment in eNOS activation [8].
Chronic treatment of apolipoprotein E −/− mice with an
A-FABP inhibitor improved endothelium-dependent relaxa-
tions in aorta studied in vitro without affecting endothelium-
independent relaxations [44].
Also resistin (or “resistance to insulin”) and visfatin
contribute to vascular disease by inducing endothelial dys-
function through a variety of mechanisms [27,45].
It should be noted that dysfunctional endothelium can in
turn alter the profile of adipo(cyto)kine secretion through
release of pro-inflammatory proteins that can act upon
adipocytes by both endocrine and paracrine mechanisms.
This positive feedback loop between the endothelium and the
adipose tissue exacerbates inflammation and promotes
progression of vascular disease [27]. It was also found in
patients that there is an independent relation between
the amount of epicardial adipose tissue and endothelial
function as assessed with flow-mediated dilation of the
brachial artery [46].
4. Adipo(cyto)kines and hypertension
Many adipo(cyto)kines have vasoactive properties and
therefore can influence blood pressure. It has been shown
that lipoatrophic mice, born without white fat tissue, have a
markedly decreased amount of perivascular adipose tissue,
increased arterial pressure and compromised vascular
function [47].
4.1. Adiponectin
Plasma adiponectin levels are paradoxically decreased in
obese subjects. Hypoadiponectinaemia has been reported as
an independent risk factor for hypertension [48,49]. In
addition, adeno-viral overexpression of adiponectin reversed
salt-induced hypertension in mice [50]. Adiponectin knockout
mice show elevated systemic blood pressure. Adiponectin
protects against hypertension through an endothelium-
dependent mechanism as adiponectin-deficient mice show
an impaired response to acetylcholine-induced vascular
relaxation [38]. This endothelium-mediated relaxing effect is
diminished with obesity [26]. Blockade of angiotensin-II type 1
receptor leads to elevation of circulating adiponectin levels in
humans, which could confer the pleiotropic beneficial effects
of angiotensin receptor blockers [51]. A recent clinical study
revealed the association between plasma adiponectin levels
1516 M ET AB O LI S M CL I NI CA L A N D EX PE R IM EN T AL 6 2 (2 0 1 3) 1 51 3–1 52 1
and the progression of arterial stiffness in hypertensive
patients [52]. Whereas some clinical studies show correlations
between systemic adiponectin concentrations and blood
pressure, there are conflicting data [53]. More studies are
needed at both the basic science and clinical level to establish
adiponectin as a primary regulator of blood pressure.
4.2. Leptin
Leptin is mainly known as a substance that through interac-
tion with the hypothalamus decreases food intake and
increases energy expenditure. However, leptin also increases
blood pressure when infused chronically in rodents [54]. In a
clinical study it was found that the free leptin index (ratio
between the concentration of leptin and the soluble leptin
receptor in plasma) may provide prognostic value towards
hypertension and cardiovascular events [55].
Obesity-associated hypertension is sometimes explained
by the leptin-resistance theory. This theory is based on the
concept that obesity is due to a failure of leptin to induce
satiety as a result of a reduced sensitivity to the hormone. This
leads to increased levels in obesity [56]. Because leptin exerts a
sympatho-excitatory effect, these high levels probably con-
tribute to the increased sympathetic nervous system activity
seen in obesity-induced hypertension [57]. It can be noted that
a large case–control study could not reveal a relation between
serum adiponectin and serum leptin levels and the risk for
preeclampsia [58].
4.3. Perivascular adipose tissue derived relaxing
factor (PVADRF)
Perivascular adipose tissue can be considered as a paracrine
organ that transduces metabolic signals from the adipose
tissue to blood vessels [59]. Perivascular adipose tissue has
anti-contractile properties and secretes transferable sub-
stances including (a) yet unidentified PVADRF(s). This anti-
contractile property is in parallel with the amount of “healthy”
adipose tissue, but is abolished with the development of
obesity [26]. In obesity, dysfunction and inflammation of
adipose tissue result in impaired production of PVADRF.
Ketonen et al. showed a critical role of ROS from perivascular
adipose tissue in the impairment of endothelium-dependent
vasodilation in diet-induced obese mice [60].
Many adipokines with anti-contractile properties, includ-
ing leptin, adiponectin, angiotensin 1–7, hydrogen sufide,
visfatin and methyl palmitate have been proposed as potential
candidates for PVADRF. However, none of them fully mimics
the vascular effects of PVADRF and its precise identity remains
to be elucidated [34,61].
Although the nature of this adipocyte-derived relaxing
factor remains to be defined, both endothelium-dependent
and -independent mechanisms seem to be involved. While
the endothelium-dependent mechanism involves nitric oxide
release and activation of calcium-dependent K+-channel, the
endothelium-independent mechanism may involve hydrogen
peroxide and subsequent activation of guanylyl cyclase [62].
Interestingly, in hypertension perivascular adipose tissue
mass and adipocyte size are decreased and the perivascular
adipose tissue exerts less anti-contractile effects. This dimin-
ished anti-contractile effect is also seen in obesity. However,
in obesity perivascular adipose tissue mass and adipocyte size
are increased. This discrepancy needs to be further investi-
gated [59].
It should be noted that perivascular adipose tissue has also
been reported to exert pro-contractile effects [63,64].
4.4. Renin–angiotensin system
Adipose tissue produces angiotensin II through a local renin–
angiotensin system. The expression of this system is elevated
in obesity [65]. Its contribution to obesity-related hypertension
is as yet not established. However there is some evidence that
adipocyte-derived angiotensinogen influences blood pressure
through an interplay with angiotensin-II receptors and
through an endocrine feedback regulation of the systemic
renin–angiotensin–aldosterone system [53].
4.5. Resistin
Several studies have suggested a relationship between
hyperresistinemia and hypertension. Serum resistin concen-
tration correlates positively to mean blood pressure in
patients with type 2 diabetes, but not in non-diabetic
hypertensive patients [66]. Several mechanisms have been
proposed for the resistin effects on blood pressure: increase in
mRNA abundance of fatty acid binding protein in endothelial
cells, promotion of smooth muscle cell proliferation and
vasocontractile properties of resistin [53].
4.6. Other
Given the vasodilating effect of omentin on blood vessels, this
adipo(cyto)kine may have a protective role in obesity-related
hypertension [67]. It should also be noted that secretory
products of human adipocytes stimulate steroidogenesis in
human adrenocortical cells, with a predominant effect on
mineralocorticoid secretion, suggesting a direct link between
obesity, the systemic renin–angiotensin–aldosterone-system
and hypertension [68].
5. Adipo(cyto)kines and atherosclerosis
The importance of adipo(cyto)kines in the atherosclerotic
process is nicely illustrated by the observation that trans-
plantation of visceral adipose tissue into apolipoprotein E−/−
mice caused a marked acceleration of atherosclerosis by
inducing the production of pro-inflammatory factors [69].
The ability of many adipo(cyto)kines to stimulate angio-
genesis is beneficial for adipose tissue growth, but less
interesting in atherosclerosis as induction of endothelial cell
proliferation and migration can lead to plaque destabilization
and rupture. In addition, excessive new blood vessel growth
can damage the surrounding tissues and newly formed
vessels are highly permeable, allowing inflammatory cells
and circulating factors to infiltrate the surrounding tissues
leading to inflammation.
Accumulation of lipid-laden foam cells and macrophage-
related inflammation are key features of atherosclerotic
 M E TAB O LI S M CL I NI CA L A N D EX P ER IM EN T AL 6 2 (2 0 1 3) 1 51 3 –1 5 21
lesions. Adiponectin is known to modulate macrophage
phenotype and function so that inflammation is resolved: it
inhibits macrophage-to-foam cell transformation, reduces
intracellular cholesteryl ester content in macrophages, sup-
presses TNFα production and stimulates the production of the
anti-inflammatory cytokine IL-10 [6]. It also facilitates the
phagocytosis of early apoptotic and dead cells by macro-
phages. In addition, adiponectin functions as a regulator of
macrophage phenotype, shifting the activated macrophage
towards an anti-inflammatory phenotype [70].
In several clinical studies in healthy and diabetic subjects,
an inverse correlation has been observed between serum
adiponectin and carotid intima–media thickness, a marker of
subclinical atherosclerosis and predictor of future myocardial
infarction and stroke [71]. In addition, there is a strong
correlation between hypoadiponectinemia and coronary
heart disease: high plasma levels of adiponectin are associat-
ed with a decreased risk of coronary heart disease, indepen-
dently of other risk factors [72].
Impairment in endothelial repair is an early step of the
atherosclerotic process. Both animal and clinical investiga-
tions suggest that adiponectin promotes endothelial repair by
increasing the number and function of endothelial progenitor
cells, which are important for endothelial repair following
vascular injury. Adiponectin stimulates survival, proliferation
and differentiation of bone marrow-derived endothelial
progenitor cells and also promotes the migration of the
endothelial progenitor cells [73]. Adiponectin counteracts
diabetes-induced damage of endothelial progenitor cells
by decreasing high glucose-induced intracellular ROS accu-
mulation [74].
Also omentin, another adipokine expressed in peri-adven-
titial epicardial adipose tissue, may play a protective role in
coronary atherosclerosis by activating eNOS [41]. Liu et al.
showed that circulating omentin levels are lower in patients
with metabolic syndrome and atherosclerosis than in patients
with metabolic syndrome but without atherosclerosis [75].
Circulating omentin may also play a role in preventing arterial
calcification, which contributes to atherosclerotic lesions [76].
Plasma A-FABP levels in humans are positively correlated
with coronary atherosclerosis and the number of stenotic
vessels in coronary artery disorders [77]. The proatherogenic
activity of A-FAPBP is mediated by its direct actions on
macrophages, independent of lipid metabolism and insulin
sensitivity. A-FABP deficiency results in a marked reduction of
aortic atherosclerotic lesions in apolipoprotein E−/− mice [78].
Pharmacological inhibition of A-FABP also significantly pro-
tected against atherosclerotic plaque formation in apolipo-
protein E−/− mice [79].
High circulating level of chemerin in humans is considered
to be a marker of inflammation and metabolic syndrome. No
association was found between chemerin levels and athero-
sclerosis [80]. However, another group showed higher levels of
chemerin in peri-aortic and epicardial adipose tissue of
patients with coronary artery disease, which suggests a role
in the progression of aortic and coronary atherosclerosis [81].
In contrast, a recent study demonstrated that chemerin plays
an inhibitory role on inflammatory state of cultured human
vascular endothelial cells by preventing the TNFα-induced
VCAM-1 expression and monocytes adhesion [82].
1517
Visfatin is a more recently identified adipokine and as yet
not completely characterized for its role in cardiovascular
disease [83]. A recent in vitro study indicates that visfatin, at
doses measurable in plasma of patients with acute coronary
syndrome, induces a procoagulant phenotype in human
coronary endothelial cells by promoting the expression of
the “tissue factor”. This supports the hypothesis that
visfatin might be a relevant player in this athero-thrombotic
disease [84].
Also resistin was found to be a strong risk factor for acute
coronary syndrome in different clinical studies [85]. Resistin
promotes proatherosclerotic changes in vascular smooth
muscle cells such as increased proliferation, migration and
contractility [27].
Considering that perivascular adipose tissue contributes to
vascular diseases, it is suggested that perivascular adipose
tissue may be a novel target for the treatment of atherosclerosis
and restenosis after coronary intervention. Restenosis at sites
of vascular injury following angioplasty is a phenomenon in
which vascular smooth muscle cell phenotype switches to
proliferation and migration as is the case in atherosclerosis.
The local microenvironment, influenced by growth factors and
inhibitors, is very important for the phenotypic conversion.
There is ample evidence that factors released from perivascular
fat regulate vascular smooth muscle cell proliferation and
migration [86]. It is also suggested that epicardial adipose tissue
may serve as a local source of pro-inflammatory cytokines
involved in the development of coronary artery disease [87,88].
It was found in patients that there is an independent
relationship between increased epicardial adipose tissue and
carotid intima–media thickness [46].
6. Adipo(cyto)kines and heart diseases
Under normal conditions, epicardial and pericardial adipose
tissues are local energy sources for the contractile activity of
the heart by releasing fatty acids through lipolysis. However,
expanded epicardial fat and pericardial fat are important risk
factors for obesity-related cardiac dysfunction [89].
Many experimental studies demonstrate that adiponectin
acts directly on cardiomyocytes to protect the heart from
ischemic injury, hypertrophy, cardiomyopathy and systolic
dysfunction [90]. These cardio-protective effects of adiponec-
tin are attributed to its ability in suppressing apoptosis,
oxidative stress and inflammation in cardiomyocytes [91].
Interestingly, adiponectin is also expressed and secreted by
cardiomyocytes, however less in patients with dilated cardio-
myopathy, suggesting an autocrine cardio-protective activity
of adiponectin [92].
While experimental studies suggest that adiponectin plays
a protective role in the cardiovascular system, epidemiological
studies reveal that high levels of adiponectin are associated
with increased mortality and severity of congestive heart
failure. A recent study reported that circulating levels of
adiponectin are associated with the clinical outcomes and
severity of heart failure. Moreover, it was found that
adiponectin is significantly expressed in the myocardium
and that its tissue expression positively correlated with the
severity of heart failure [93]. These results are completely
1518 M ET AB O LI S M CL I NI CA L A N D EX PE R IM EN T AL 6 2 (2 0 1 3) 1 51 3–1 52 1

opposite to the expectation based on the beneficial effects of
adiponectin. It is still controversial whether increased adipo-
nectin production is a bystander or a key mediator in the
development of heart failure. It is suggested that increased
adiponectin production in patients with heart failure is a part
of compensatory mechanisms against oxidative stress and
inflammation and that the increase in adiponectin in patients
with advanced heart failure might be related to a complicated
“adiponectin resistance”. It has been suggested that with
aging and progression of chronic cardiovascular diseases the
organism becomes more resistant to adiponectin. Increased
adiponectin production might contribute to the metabolic and
structural remodeling of the failing heart. As yet it is still
inconclusive whether increased adiponectin production
plays a detrimental role or a protective role in cardiac heart
failure [94].
The secreted form of A-FABP has been identified as a major
cardiodepressant factor that confers the suppressive effect of
adipocytes on cardiac contractile functions [95]. On the other
hand evidence from clinical and in vitro studies suggests that
omentin-1 has cardioprotective properties in patients with
type-2 diabetes [96].
Many studies suggest that resistin is detrimental to the
function of cardiac myocytes. This would occur by several
mechanisms: decreased glucose uptake, hypertrophy, de-
creased contractility and altered Ca2+-handling, increased
ROS production and apoptosis [97].
While obesity is a recognized risk factor for atrial fibrillation,
only recent research unraveled the mechanism behind this
association. Several studies report an association between the
volume of epicardial adipose tissue and atrial fibrillation [98].
Very recently Nakanishi et al. demonstrated that the volume of
peri-atrial epicardial adipose tissue better predicts atrial
fibrillation events than the total volume of epicardial adipose
tissue [99]. This suggests that peri-atrial adipose tissue may
have a direct effect on atrial function via release of adipo(cyto)
kines that may trigger fibrillation. Strategies to reduce peri-
atrial adipose tissue volume might be effective in decreasing
the incidence and recurrence of atrial fibrillation.
7. Concluding remarks (Fig. 1)
The combat against cardiovascular diseases is challenged by
the escalating global epidemic of obesity (“globesity”) and
excess adipose tissue. Adipose tissues secrete adipo(cyto)
kines that activate many different pathways in various cell
types that regulate the cardiovascular circulatory system.
These adipo(cyto)kines can exert opposite effects on cardiac
and vascular functions. It is the sum of these functional
changes that ultimately will determine the overall impact on
the cardiovascular system [27].
While adiponectin and omentin are rather protective,
many other adipo(cyto)kines promote obesity-related cardio-
vascular diseases. Unbalanced production of the adipo(cyto)
kines, as occurs when adipose tissue develops adiposopathy,
is an important risk factor for the development of cardiovas-
cular diseases. It seems that hypoxia and inflammation are
key cornerstones in the process controlling the delicate
balance of secretion of “good” and “bad” adipo(cyto)kines.
The exact role of the different potential players and of the
different types of fat depots in the body is still unclear.
Recognizing the pathogenic potential of adipose tissue
provides a scientific foundation to treat adiposopathy and
helps validate the concept that the development of anti-
obesity agents must not only reduce fat mass (adiposity) but
also must correct fat dysfunction (adiposopathy) [13]. There is
indeed evidence that the type of adipose tissue is more
important than the absolute amount of body fat in determin-
ing the risk of obesity-related diseases. The accumulation of

Fig. 1 – Influence of adipose tissue on the cardiovascular system. Figure illustrates that normal adipose tissue is beneficial
for the cardiovascular system by releasing “healthy” adipo(cyto)kines. Excess of energy intake leads to adiposopathy
characterized by adipocyte hypertrophy, macrophage infiltration and insufficient blood flow resulting in hypoxia. This favors
the release of “unhealthy” adipo(cyto)kines, deleterious for the cardiovascular system.
 M E TAB O LI S M CL I NI CA L A N D EX P ER IM EN T AL 6 2 (2 0 1 3) 1 51 3 –1 5 21
ectopic fat in the liver might be a good marker of adipose
tissue pathology [100].
The growing understanding in the relation between obesity
and cardiovascular diseases must emerge in innovative
therapies to control the complications of obesity. This will
most likely be as adjuncts to what remains the mainstay of
obesity management: exercise and a low fat intake. The
understanding that adipose tissue becomes deleterious in
obesity may be a concept that might be helpful to explain to
patients the necessity of body weight reduction so that the
“unhealthy” fat is healed into “healthy” fat. As adipocyte
dysfunction is recognized as a key element in the pathophys-
iology of cardiovascular diseases in obesity, interventions that
correct adipose tissue function should provide benefits by
slowing or preventing cardiovascular disease progression. In a
recent study it was demonstrated that an intermittent fasting/
calorie restriction regimen improves risk factors for coronary
heart disease and that this is related to modulations in
adipokine concentrations [101].
Future research is challenged by attempting to restore
adipose cells in obesity to their pre-morbid properties by
drugs, exercise, diets, bariatric surgery…. Several recent
studies have investigated the effect of hypocaloric diets and
various dietary factors on adipo(cyto)kines. So it was found
that the “healthy” adiponectin is increased after a diet rich in
α-linoleic acid which is found in various plant source foods.
This is also the case with grape seed extract, soybean, dietary
fiber, exercise and weight loss [102]. Additional studies will be
required to establish the effects of these “nutraceuticals” on
cardiovascular disease. Huang et al. showed that margarine-
derived trans fatty acids diets fed to male rats decreased
plasma levels of adiponectin and increased resistin and leptin
levels [103]. Targeted ablation of the vasculature that feeds
adipose tissue might not only cause weight reduction and
metabolic normalization [104], but can also be a new option in
the treatment of obesity-associated cardiovascular disorders.
Tipping the balance from pro-inflammatory to anti-inflam-
matory adipo(cyto)kines by drugs is another way to counter
obesity-related cardiovascular diseases. In this respect it is of
interest that thiazolidinediones, telmisartan, angiotensin-
converting enzyme inhibitors, rimonabant and taranabant
all increase the level of adiponectin [105], which may
contribute to their cardiovascular protective effects.
Whatsoever, many research efforts are still required to
unravel the complex relation between adipose tissue and
cardiovascular diseases and the potential role of adipo(cyto)
kines as biomarkers. This may yield new tools to improve
health in the next generations.
Acknowledgments
This work was supported by grants from FWO-Vlaanderen,
the Bijzonder Onderzoeksfonds (BOF) of Ghent University and
Geconcerteerde Onderzoeks Actie (GOA) of Ghent University.
Conflict of interest
Disclosure: no conflict of interest.
1519
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