Adipose Tissue and Atherosclerosis

Abstract

High-energy intake which exceeds energy expenditure leads to the accumulation of triglycerides in adipose tissue, predominantly in large-size adipocytes. This metabolic shift, which drives the liver to produce atherogenic dyslipidemia, is well documented. In addition, an increasing amount of monocytes/macrophages, predominantly the proinflammatory M1-type, cumulates in ectopic adipose tissue. The mechanism of this process, the turnover of macrophages in adipose tissue and their direct atherogenic effects all remain to be analyzed. © 2015 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic.

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PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)
 2015 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic
Fax +420 241 062 164, e-mail: physres@biomed.cas.cz, www.biomed.cas.cz/physiolres
Physiol. Res. 64 (Suppl. 3): S395-S402, 2015
REVIEW
Adipose Tissue and Atherosclerosis
R. POLEDNE1, I. KRÁLOVÁ LESNÁ1, S. ČEJKOVÁ1
1Laboratory for Atherosclerosis Research, Centre of Experimental Medicine, Institute for Clinical
and Experimental Medicine, Prague, Czech Republic
Received July 17, 2015
Accepted July 31, 2015
Summary
High-energy intake which exceeds energy expenditure leads to
the accumulation of triglycerides in adipose tissue, predominantly
in large-size adipocytes. This metabolic shift, which drives the
liver to produce atherogenic dyslipidemia, is well documented.
In addition, an increasing amount of monocytes/macrophages,
predominantly the proinflammatory M1-type, cumulates in
ectopic adipose tissue. The mechanism of this process, the
turnover of macrophages in adipose tissue and their direct
atherogenic effects all remain to be analyzed.
Key words
Adipose tissue • Dyslipidemia • Inflammation • Macrophages
Corresponding author
R. Poledne, Laboratory for Atherosclerosis Research, Centre of
Experimental Medicine, Institute for Clinical and Experimental
Medicine (IKEM), Videnska 1958/9, 140 21 Prague 4, Czech
Republic. E-mail: rudolf.poledne@ikem.cz
Adipose tissue and dyslipidemia
For a long time it has been evident that adipose
tissue is a store of energy reserved for acute needs during
inadequate energy intake. Numerous reviews describe the
disease known as “adiposopathy” as the consequences of
obesity (Bays 2011). High-density energy in adipocyte
triglycerides is a very suitable energy substrate and free
fatty acids (FFA) released by hormone-sensitive lipase
(Zimmerman et al. 2009) are an immediate emergency
source of energy in the beta-oxidation of muscle and
hepatic mitochondria. During long time development of
men this energy source was principal question of life and
death contrary to recent situation when we are not in the
real fasting status.
A disequilibrium between high-energy intake
and low expenditure leads to adipose tissue accumulation,
which in a work from more than 70 years ago was found
to be connected to cardiovascular disease (Vague 1947).
The accumulation of triglycerides (TG) in ectopic fat is
now considered most likely its main cause and the most
frequent pathology in men. Insulin deficiency is a key
player in what is known as “metabolic syndrome”, first
described in detail two decades ago (Reaven 1994).
Consequently, hormone-sensitive lipase is inadequately
inhibited in adipose tissue during postprandial status
(Shulman 2014). FFA is released into circulation, unused
for energy production and the excess of which are fished
out in the liver. Hepatocytes are then able to store them in
the form of depot TGs (Donnelly et al. 2005). This
produces a special type of fat vacuole in hepatocytes,
which can develop into non-alcoholic liver steatosis
(Cohen et al. 2011). Currently, it is probably the most
frequent pathology in industrialized countries (but
probably also in some developing countries of the Middle
East and India). Hepatocytes try to counteract TG
accumulation by accelerating intracellular TG transport in
the form of very low-density lipoproteins (VLDL) and
secreting them into circulation (Adiels et al. 2006). These
types of VLDLs possess a much higher TG content
(calculated for one molecule carrier of apoprotein B),
they possess also an increased relationship of TG to
cholesterol esters and are consequently a much poorer
substrate for lipoprotein lipase on the surface of
endothelial cells. This enzyme is responsible for splitting
TG VLDL particles (as well as chylomicrons) and their

S396 Poledne et al. Vol. 64
consequent change to low density lipoproteins (LDL).
TG-rich VLDLs and their remnants are accumulated in
circulation, which increases TG concentration in the
fasting status, but namely the postprandial status. They
are also believed to be atherogenic over a long period.
Recent large epidemiological studies have been able to
confirm their atherogenic effect (Langsted et al. 2011).
The atherogenic effect of remnant lipoproteins produced
by slower lipolysis of TG in TG-rich VLDLs is
accompanied by a decreased rate of LDL production
(Boren et al. 2014). These “small dense LDL particles”
are substantially pro-atherogenic, since their entrance into
the arterial wall is easier, and may also display a high
probability of oxidation.
This type of typical dyslipidemia, which is
prevalent in “rich” societies, is very frequently combined
with insulin resistance and liver steatosis, but primarily
with the enlargement of visceral adipose tissue, which
produces large TG-rich VLDLs (DiPietro et al. 1999).
The primary reason for these metabolic pathways is the
accumulation of TG in adipose tissue, which produces
very large adipocytes. This phenotype of large adipocytes
and dyslipidemia is combined with chronic
proinflammatory status, decreased sensitivity to insulin
(Xu et al. 2003) and, consequently, liver steatosis and TG
accumulation in hepatocytes. The main reason for
proinflammatory status is the conclusive changes in
adipose tissue, as documented recently. Although
hepatocytes and muscle cells also exhibit obesity-induced
proinflammatory status (Shulman 2014), white adipose
tissue plays a key role in the development of
proinflammatory status.
A new role of adipose tissue
A new role of adipose tissue was described more
than two decades ago. Firstly, a new role of leptin, as
a hormone that affects appetite and individual hunger
feelings, was described (Liuzzi et al. 1999). Later it was
documented that adipocytes produce a number of
molecules among them interleukin 6 and tumor
necrosis factor α – two cytokines which stimulate
proinflammatory status of the whole organism. It is now
well known that adipose tissue produces more than
50 cytokines and hormones (Kershaw and Flier 2004) as
well as signal molecules (adipokines). These have either
an autocrine or paracrine function, which affect numerous
processes related to energy homeostasis, glucose
metabolism but also immune reaction.
This is one part of proinflammatory activity of
adipose tissue related to the activity of adipocytes.
Adipose tissue contains large amounts of white line cells
in addition to adipocytes, which enter and leave adipose
tissue continuously and represents the second part
of proinflammatory effect. A certain proportion of
monocytes/macrophages (MO/Mφ) are always present
within adipose tissue, but their number increases after the
effect of numerous pathophysiological stimuli on lipid
metabolism. An increased amount of MO/Mφ in white
adipose tissue is also produced by the short-term feeding
of a TG-rich diet. In any case, the amount of these cells is
increased in chronic over-nutrition when the normal
physiological capacity of adipocytes is exceeded, which
progresses to an unusually large amount of adipocytes
leading to stress and cellular dysfunction (Ogedaard et al.
2007). The reasons for an excess of physiological
homeostasis of adipocytes and the development of
unusually large adipocytes after high FFA inflow are still
not known. One possible reason discovered recently
(Ferranter 2013) is associated with their individual ability
to buffer high FFA inflow. Via their scavenger function,
these cells are able to absorb a shock of FFA inflow in
postprandial status, changing to proinflammatory status
when the buffer capacity is permanently crossed over
(namely in insulin inadequate/lower sensitivity).
This buffering capacity of MO/Mφ depends not
only on the presence of these molecules in adipose tissue,
but namely on their absolute number and ratio to
adipocyte mass. The proportion of MO/Mφ cells in
adipose tissue normally reach several percent under
physiological conditions, but can reach a ratio of 1:1 for
obesity and for a maximal size of adipocytes. Therefore,
in long-term obese individuals, MO/Mφ represents 50 %
of all cells of white adipose tissue.
Heterogeneity of macrophages
The family of MO/Mφ in adipose tissue is very
non-homogenous as well as in other pathological statuses.
Besides normally stimulated proinflammatory
macrophages, named M1, anti-inflammatory alternatively
stimulated M2 macrophages are also present, which do
not produce inflammatory adipokines (Italiani and
Boraschi 2014). In adipose tissue of lean experimental
animals, anti-inflammatory M2 cells are predominantly
presented (Lumeng et al. 2007), whereas obesity induced
by a high-fat diet drives adipose tissue to cumulate
proinflammatory M1 macrophages (Weisberg et al.

2015 Adipose Tissue and Atherosclerosis S397
2003). Differentiation between these two statuses has
been generally accepted and discussed in the recent
literature. However, a concrete phenotype description of
M1 and M2 cells based on a definition of different
surface markers is rather unclear. Classically activated
M1 macrophages are stimulated by interferon gamma
(IFNγ) produced by Th1 cells. They predominantly
express phagocytic activity and represent a natural
defense against bacterial and parasitic infections (Stöger
et al. 2010). These phagocytising cells produce a large
number of proinflammatory cytokines, such as tumor
necrosis factor (TNFα), Il-13 and Il-18 (Martinez et al.
2008) and are potentially proatherogenic. In contrast,
anti-inflammatory M2 macrophages are stimulated by the
product of Th2 cells (Il-3 and Il-14) and have a buffering
effect during long lasting chronic infections. Although
a phenotype differentiation between M1 and M2
macrophages has not been resolved, it has been
documented that M1 macrophages mainly produce NO,
whereas M2 macrophages mainly produce ornithine as
a final metabolite of arginine in two different pathways.
Recent studies (Mills 2012) have gone so far as to
propose that the ratio of M1/M2 macrophages might play
a pivotal role in the most frequent pathologies (cancer
and atherosclerosis) and is able to influence the average
length of life in men. In contrast to external antigens (in
typical infection diseases), the M1/M2 ratio plays the
main role in these two pathologies. This ratio works in
synchronicity with a number of Th1 and Th2 cells and
indicates a status known as “innate immunity”.
Research in this field has enlarged substantially
in the last number of years and the number of related
publications has risen in geometric order. The main parts
of these in vitro studies analyze several different
regulations for proinflammatory factors (which also
include the nutritional effect of saturated fatty acids).
However, an exact definition of the phenotype of
phagocytising M1 and anti-inflammatory effective M2 is
not still clear. Expression of M1 and M2 has been used in
numerous review articles related to this problem without,
however, correctly defining both phenotypes (Stöger et
al. 2010, Mallat 2014, Suganami and Ogawa 2010). It is
also very probable that adipose tissue also contains
another phenotype between M1 and M2 (Stöger et al.
2010) and may be presented in actual non-stationary
situations with the possibility of one phenotype being
changed to another (Mallat 2014). It is still not clear how
an inflow of macrophages into adipose tissue changes the
acute amount of macrophages on the one side or if an
outflow of these cells (after a certain residential period)
from the tissue is more important. It has been proposed
that all tissue-resident macrophages are fully
differentiated (Taylor et al. 2005), but it has been
documented recently (Mulder et al. 2014) that spleen-
derived macrophages are readily polarized to M1 and M2
under different external influences. It might be proposed
that macrophages which release adipose tissue after
a certain residence period possess more proinflammatory
phenotypes compared to cells that enter the tissue from
circulation. Then these macrophages might translate
proinflammatory signals to other organs, namely the
arterial wall.
Macrophages and the arterial wall
A central role of MO/Mφ in atherogenesis was
first described in the pioneering work of Goldstein and
Brown (Goldstein and Brown 1987), founders of the
theory of plasma cholesterol regulation due to specific
apoB receptors. This laboratory also described scavenger
receptors for apoB containing particles on the surface of
macrophages (Brown and Goldstein 1983). These
receptor macrophages clean the subendothelial space of
large and medium size arteries from abundant LDL
particles and are able to maintain the physiological
equilibrium of the arterial wall between the actual needs
of the cholesterol molecule on the one hand and the
adequate or in-adequate inflow of LDL-carrying particles
in hypercholesterolemia on the other. It has been accepted
for quite some time that in addition to lipid disorders,
inflammation and the central role of macrophages are an
integral part of atherosclerosis pathology (Lohmann et al.
2009).
Adipose tissue and, especially, obese adipose
tissue influence the adhesion of monocytes (and other
immune-competent cells) to endothelial cells and their
migration to the arterial wall. Adipose tissue is composed
of not only adipocytes, but also a number of other
cell types such as fibroblasts, endothelial cells,
immunocompetent cells and many others. But adipocytes
are the main producers of adipokines (leptin, adiponectin,
resistin, visfatin, etc.), a subtype of the cytokine family.
The adipokines produced in adipocytes stimulate
production of adhesion molecules (mainly intercellular
adhesion molecule ICAM-1, vascular cell adhesion
molecule VCAM-1), which in turn increases the adhesion
of monocytes to the endothelium (Kawanami et al. 2004,
Manuel-Apolinar et al. 2013, Mattu and Randeva 2013).

S398 Poledne et al. Vol. 64
These cells can up-regulate various mediators of vascular
inflammation like TNFα, IL2, IL6 and macrophage
chemotactic protein MCP-1 from endothelial cells and
peripheral blood mononuclear cells (Bouloumie et al.
1999). Adiponectin, which is also produced by adipose
tissue, plays the opposite role. It is considered an anti-
atherogenic adipokine, which is produced in lower
amounts in obese subjects and influences eNOS (Adya et
al. 2015). Generally, chronic inflammation and adipose
tissue metabolic dysfunction (e.g. higher production of
proinflammatory factors or soluble adhesion molecules)
influence the endothelium and increase its adhesiveness
to monocytes.
Trapping of macrophages in the subendothelium
of the vascular wall is influenced by a number of proteins
produced by macrophages themselves. One of these
factors is macrophage colony stimulated factor (MCSF)
and macrophage chemotactic factor (MCF) with similar
effect. Activation of macrophages as a result of their
atherogenic function is induced by interferon gamma
(IFNγ) produced by Th1 cells (Gupta et al. 1997).
Increased production of these molecules traps
macrophages in the interstitial space between smooth
muscle cells. Consequent to this process, residential
macrophages appear and further develop as foam cells.
Also, several surface receptors on macrophages are able
to influence mobility of these molecules in the
subendothelium. Post-translation glycosylation of one
of these receptors (CcR5) substantially stimulates
atherogenesis (Scott et al. 2012). In contrast, a decrease
of glycosylation inhibits atherogenesis in genetically
modified knock-out mice for this protein (Cambadiere et
al. 2008). Similarly, surface receptor Cx3cr on platelets
influences macrophage differentiation and is also
stimulated by hypercholesterolemia (Cambadiere et al.
2008). This represents a new mechanism of trapping
macrophages in the arterial wall (Postea et al. 2012).
Recently, a new macrophage-producing protein, netrine1,
has been described (Van Gills et al. 2012). It is of interest
that its expression in macrophages is stimulated
intracellularly by saturated fatty acids. This might
indicate an additional atherogenic effect of SAFA in
addition to their well-known influence on
hypercholesterolemia.
Differentiation of monocytes to macrophages
and then to residential macrophages within the
subendothelial space of the arteries is a central process of
atherogenesis and is regulated by a number of
transcription factors. One of the important factors of
differentiation is caveolin (a structural protein of
intracellular caveloae), which stimulates transcription of
several proinflammatory mediators and surface receptors
of macrophages (Fu et al. 2012). It also stimulates
synthesis of CD36 on the macrophage surface. This
receptor is stimulated at the same time by oxidized LDL
(Park et al. 2009) leading to the acceleration of
atherogenesis through a combination of environmental
effects (high intake of alimentary saturated fat) on
stimulated proinflammatory macrophages as well as
hypercholesterolemia.
Development of macrophages into foam cells
Differentiation of MO/Mφ is always combined
with phagocytic activity, so it is understandable that
production of foam cells is substantially potentiated by
abundant LDL particles within the arterial wall
(Gauderaut et al. 2012). Continuation of the scavenger
process of macrophages and their growth due to
consumption of further abundant LDL particles lead to
their gradual change to resident macrophages and
consequently to foam cells. Although this process might
be primarily protective (for a temporarily increased
inflow of cholesterol-carrying particles) in situations
where there is long-lasting accelerated transport of LDL
particles to the arterial wall (and more if these particles
are oxidized within the subendothelium), it also leads to
the growth of fatty streaks and further development of
atherosclerosis and apoptosis of some foam cells which
stimulate inflammation and proliferation of smooth
muscle cells (Lussis 2000). Two other negative effects on
atherogenesis have been documented: a decrease of
activity of reverse cholesterol transport (Reiss and
Cronstein 2012) and an increase of intravasal triglyceride
concentration and their accumulation in macrophages of
the arterial wall. Remnants of very low-density
lipoprotein (VLDL) particles are able to enter the arterial
wall and are scavenged in macrophages (Bojic et al.
2012). This process also stimulates production of
proinflammatory cytokines and further worsens
proinflammatory status within the arterial wall. This
explains recently proven effect of postprandial
triglyceride concentration on myocardial infarction
mortality (Langsted et al. 2011).
Perivascular adipose tissue
Recently, a new possible atherogenic effect of

2015 Adipose Tissue and Atherosclerosis S399
adipose tissue surrounding large and middle size arteries
has been described. Perivascular adipose tissue differs
from other adipose tissue by the certain presence of
brown adipocytes alongside their white variants (Szasz
and Web 2012). It is more vascularized and displays
different characteristics in different parts of the body
(Chatterjee et al. 2009). Several laboratories have
analyzed the possible effect of perivascular fat on vessel
wall reactivity. Both positive (Rittig et al. 2008) as well
as negative (Reifenberger et al. 2007) effects have been
described. These differences of perivascular tissue
influence on arterial wall reactivity may be mediated by
free fatty acids released from adherent adipose tissue.
Increased activity of triglyceride lipase furnishes free
fatty acids directly to the arterial wall, which induces
endothelial dysfunction. Contrary in experimental model
of mouse without functioning lipase (triglyceride lipase
KO) no endothelial dysfunction appeared (Zimmermann
et al. 2009).
The negative effect of perivascular adipose
tissue on atherosclerosis progression was described in
a morphological analysis of 16 human hearts post-
mortem (Verhagen et al. 2012). An increased volume of
adipose tissue surrounding atherosclerotic lesions of the
coronary artery was found together with an increase of
the tissue concentration of lymphocytes. An increased
volume of perivascular adipose tissue was also found in
patients with coronary atherosclerosis documented by
computer tomography (Greif et al. 2009).
In contrast to the results of Greif, we did not find
any difference in the volume of perivascular adipose
tissue surrounding the coronary artery, when groups with
(ischemic heart disease) and without atherosclerosis
(dilation cardiomyopathy) were compared (Kralova
Lesna et al. 2015). Conversely, we were able to find
a correlation of monocyte infiltration of the coronary
artery to macrophage content in surrounding adipose
tissue in patients with ischemic heart disease, whereas no
such type of correlation in patients transplanted for
cardiomyopathy was found. It is questionable whether the
accelerated deposit of ectopic fat surrounding the artery
influences coronary atherosclerosis per se, or if some
other environmental effects are at play. In a large
epidemiological study – the Framingham Heart Study
(Lehman et al. 2010) – the volume of perivascular
adipose tissue correlated with several risk factors of
atherosclerosis (BMI, waist circumference, total and
visceral fat volume and fasting glycemia). This suggests
that the apparent direct effect of PVAT might relate to
other risk factors of cardiovascular disease and
proinflammatory status. In our above-mentioned study,
we document that the volume of PVAT depends on
a change to BMI during the last two years before
transplantation, irrespective of the original diagnosis
for transplantation (ischemic heart disease or
cardiomyopathy).
Conclusion
The two main atherogenic effects of enlarged
ectopic adipose tissue are dyslipidemia and chronic
proinflammatory status. The relationship of dyslipidemia
to the acceleration of the atherogenic process has already
been well documented and the causality of small LDL
particles in this process has been proved. On the other
hand, the effect of ectopic fat on atherogenesis due to
proinflammatory status has not been discovered yet. The
loss of immune regulation in obesity-associated adipose
tissue has been found, but its atherogenic effect is still not
understood and, of course, there is still no proof of
causality. Several anti-inflammatory agent studies are
underway but no results have been released. However,
this does not mean that maintaining BMI in the desirable
range and decreasing ectopic fat volume should not be
very important issues for preventive cardiology.
Conflict of Interest
There is no conflict of interest.
Acknowledgements
This work was supported by the research project MH CZ
- DRO (Institute for Clinical and Experimental Medicine
– IKEM, IN 00023001) and NT14009-3 of the Internal
Grant Agency of the Ministry of Health of the Czech
Republic.
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