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PPAR Res. 2007; 2007: 95974. | PMCID: PMC1783744 |
PPARs, Obesity, and Inflammation Rinke Stienstra, Caroline Duval, Michael Müller, and Sander Kersten* Nutrition, Metabolism and Genomics Group and Nutrigenomics Consortium, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands Received September 15, 2006; Revised November 13, 2006; Accepted November 13, 2006. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall. The prevalence of obesity worldwide has progressively
increased over the past decades. In 2000, it
was estimated that more than half of US adults were overweight,
while the frequency of obesity, which is defined by a body mass
index (BMI) ≥ 30 kg/m 2, was 20%, reflecting an
increase of 61% within 10 years [ 1]. Not only have more and more adults become obese, obesity is also striking at a much
younger age leading to a high number of obese children and
adolescents [ 2]. Unless drastic action is taken, many
countries will face a decline in life expectancy in the 21st
century due to the obesity epidemic. Obesity is the direct result of an imbalance between energy intake
and energy expenditure. The excess energy is primarily stored in
adipose tissue in the form of triglycerides. Although adipocytes
are specifically designed to store energy and easily fill up with
fat, the morphological changes associated with adipose tissue
growth are not without consequences for the organism as a whole
[ 3]. Evidence has accumulated suggesting that in response to
adipocyte hypertrophy during development of obesity,
adipose tissue function is compromised. Obesity also provokes structural and metabolic alterations in
other organs, including skeletal muscle and liver. Indeed, obesity
is closely linked to fat storage in liver and is nowadays
considered as a major risk factor for the development of fatty
liver diseases. The incidence of nonalcoholic fatty liver
disorders (NAFLDs) and obesity are therefore intimately linked. It
has been estimated that about 75% of obese subjects have NAFLD
while 20% develop nonalcoholic steatohepatitis (NASH), which is
defined as fatty liver disease with inflammation [ 4]. The amount of fat stored in liver is determined by the balance between
fatty acid uptake, endogenous fatty acid synthesis, triglyceride
synthesis, fatty acid oxidation, and triglyceride export. Changes
in any of these parameters can affect the amount of fat stored in
liver. The excessive fat accumulation in adipose tissue, liver, and other
organs strongly predisposes to the development of metabolic
changes that increase overall morbidity risk. The metabolic
abnormalities that often accompany obesity include hypertension,
impaired glucose tolerance, insulin resistance leading to
hyperinsulinemia, and dyslipidemia. Collectively, these
abnormalities have been clustered into the metabolic syndrome or
Syndrome X [ 5]. Individuals that are diagnosed with metabolic syndrome have a significantly increased risk of developing
cardiovascular disease (CVD) and type II diabetes. Inasmuch as CVD
is the major cause of death in industrialized countries, effective
strategies to curtail the number of individuals with metabolic
syndrome are badly needed. Visceral obesity, which is
characterized by excess fat storage in and around the abdomen, is
the prime cause of the metabolic abnormalities, and therefore
represents an important target in the treatment of metabolic
syndrome [ 6]. In recent years, it has become clear that obesity also gives rise
to a heightened state of inflammation. The link between obesity
and inflammation was first established by Hotamisligil et al. who
showed a positive correlation between adipose mass and expression
of the proinflammatory gene tumor necrosis factor- α
(TNF α) [ 7]. The link between obesity and inflammation has been further illustrated by the increased plasma levels of
several proinflammatory markers including cytokines and acute
phase proteins like C-reactive protein (CRP) in obese individuals
[ 8, 9]. Nowadays, CRP is considered as an independent
biomarker for the development of CVD [ 10] which emphasizes the connection between inflammation, obesity, and CVD. Many of the
inflammatory markers found in plasma of obese individuals appear
to originate from adipose tissue [ 8]. These observations have led to the view that obesity is a state of chronic low-grade
inflammation that is initiated by morphological changes in the
adipose tissue. One consequence of the elevated inflammatory status is insulin
resistance. Proinflammatory cytokines originating from fat have
been shown to directly interfere with insulin signaling pathways
[ 11]. For example, TNF α causes insulin resistance by inhibiting tyrosine phosphorylation of insulin receptor
substrate-1 (IRS-1) [ 12]. Other mechanisms of inhibition of IRS-1 phosphorylation by inflammatory mediators include chronic
activation of JNK, PKC, and IKK [ 13– 15]. Besides TNF α, adipose tissue produces a host of other
adipokines with well-described effects on metabolism and
inflammation. Resistin, adiponectin, leptin, and monocyte
chemoattractant protein-1 (MCP-1) are among a group of secreted
proteins from adipose tissue with immune-modulating functions
[ 16]. The production and secretion of these adipokines are altered during obesity, resulting in a more proinflammatory or
atherogenic secretion profile. Indeed, whereas secretion of MCP-1,
resistin, and other proinflammatory cytokines is increased by
obesity, the adipose secretion of the anti-inflammatory protein
adiponectin is decreased [ 17]. Although increased visceral fat depots [ 6] and adipocyte hypertrophy [ 3] had been linked to a higher degree of adipose inflammation, until recently the exact pathways leading to a
proinflammatory state of adipose tissue in obese individuals
remained unidentified. However, recently much attention has been
diverted to the role of macrophages. In 2003, two papers published
back to back showed that diet-induced obesity is associated with
infiltration of macrophages into white adipose tissue
[ 18, 19]. Infiltrated macrophages, which are part of the
stromal vascular fraction of adipose tissue, are subsequently
responsible for the production of a wide variety of
proinflammatory proteins including MCP-1, TNF α, and
interleukin-6 (IL-6). The development of insulin resistance in
adipocytes was closely linked to the infiltration of macrophages.
However, if and how entry of macrophages into white adipose tissue
(WAT) leads to systemic insulin resistance remains unclear,
although it is increasingly believed that altered secretion of
adipokines by WAT during obesity may represent an important piece
of the puzzle. One of the other tissues that is affected by the enlargement and
proinflammatory secretion profile of adipose tissue is the liver.
Chronic activation of the master regulator of inflammation nuclear
factor- κB (NF- κB) by cytokines has been directly
linked to the development of insulin resistance in liver [ 20, 21]. It has also been shown that adipose-specific overexpression
of MCP-1 increases hepatic triyglyceride content [ 22]. Although steatosis is a common occurrence in obese individuals,
the role of inflamed adipose tissue in development of steatosis
needs further exploration. Initially characterized by excess fat storage, steatosis can
progress to steatohepatitis and finally leads to cirrhosis and
structural alterations of the liver [ 23]. The molecular mechanisms underlying the development of steatosis and progression
to steatohepatitis remain poorly understood. Whereas some patients
only develop steatosis, others develop steatohepatitis and
fibrosis. Lipid peroxidation, cytokines, and other proinflammatory
compounds are believed to play a vital role in the transition
[ 4]. In addition, the role of the expanding adipose tissue
might also prove relevant to the development of steatohepatitis. Recently, the elevated inflammatory status of adipose tissue and
concurrent increased production of adipose tissue-derived
cytokines have also been connected with atherosclerosis. Initially
defined as a pathological lipid deposition, the atherosclerotic
process is nowadays considered as an ongoing inflammatory process
in which numerous cytokines, chemokines, and inflammatory cells
participate [ 24]. Independent of its connection to the metabolic syndrome, obesity itself is a known risk factor for the
development of atherosclerosis and CVD [ 25]. In summary, obesity represents a major health threat, and effective
therapies to minimize obesity-related comorbidities are sorely needed. By
targeting the inflammatory component, the progression of obesity towards
insulin resistance and CVD might be slowed down. The ligand-activated transcription factors belonging to the
peroxisome proliferators- activated receptor (PPAR) family are
involved in the regulation of inflammation and energy homestasis
and represent important targets for obesity, obesity-induced
inflammation, and metabolic syndrome in general. These receptors
share a common mode of action that involves heterodimerization
with the nuclear receptor RXR and subsequent binding to specific
DNA-response elements in the promoter of target genes. Binding of
ligands to PPARs leads to recruitment of coactivators
and chromatin remodeling, resulting in initiation of
DNA transcription [ 26, 27]. Currently, synthetic PPAR agonists
are widely used for the treatment of insulin resistance and
dyslipidemia. This review will explore the role of PPARs in
governing chronic inflammation with special emphasis on the
connection with metabolic syndrome. The link with obesity and
inflammation will be discussed separately for the three PPAR
isoforms: PPAR α, PPAR β/ δ, and PPAR γ. PPAR α is well expressed in metabolically active tissues
including liver, brown adipose tissue, muscle, and heart. In
addition, PPAR α is expressed in cells involved in immune
responses including monocytes, macrophages, and lymphocytes
[ 28]. Activation of PPAR α occurs through a variety of natural agonists, including unsaturated fatty acids and
eicosanoids, whereas fibrate drugs act as synthetic agonists. In
liver, PPAR α plays a pivotal role in fatty acid catabolism
by upregulating the expression of numerous genes involved in
mitochondrial fatty acid oxidation, peroxisomal fatty acid
oxidation, and numerous other aspects of fatty acid metabolism in
the cell [ 28]. As a consequence, activation of PPAR α
can prevent and decrease hepatic fat storage [ 29– 32].
Other metabolic pathways under control of PPAR α include
gluconeogenesis [ 33], biotransformation [ 34], and
cholesterol metabolism [ 35]. While the function of
PPAR α in mouse liver is relatively well defined, much less
is known about its role in human liver. Experiments with
“humanized” PPAR α mice have revealed that there are
intrinsic differences in the properties of the human and mouse
PPAR α protein [ 36]. In general, research on the role of PPAR α in human liver is hampered by the low expression
levels of PPAR α in human hepatoma cell lines
[ 37]. Besides governing metabolic processes, PPAR α also
regulates inflammatory processes, mainly by inhibiting
inflammatory gene expression. Hepatic PPAR α activation has
been repeatedly shown to reduce hepatic inflammation elicited by
acute exposure to cytokines and other compounds. In recent years,
several molecular mechanisms responsible for the immunosuppressive
effects of PPAR α have been uncovered [ 38]. These include interference with several proinflammatory transcription
factors including signal transducer and activator of transcription
(STAT), activator protein-1 (AP-1), and NF- κB by
PPAR α [ 39]. The latter mechanism involves stimulation of expression of the inhibitory protein I κB α,
which retains NF- κB in a nonactive state, leading to
suppression of NF- κB DNA-binding activity [ 40]. Detailed molecular studies have further revealed that PPAR α diminishes the activity of the proinflammatory transcription
factor CAATT/enhancer binding proteins (C/EBP) via sequestration
of the coactivator glucocorticoid receptor-interacting
protein-1/transcriptional intermediary factor-2 (GRIP1/TIF2)
[ 41]. Finally, PPAR α can also inhibit cytokine signaling pathways via downregulation of the IL-6 receptor
[ 42] and upregulation of sIL-1 receptor antagonist
[Stienstra et al., in press], leading to diminished inflammatory responses.
Interestingly, in humans, specific PPAR α activation using
fenofibrate has been shown to decrease plasma levels of several
acute phase proteins that are normally increased during
inflammatory conditions [ 42]. 2.1. PPARα and steatosis In mice fed a high-fat diet, proper functioning of PPAR α
is essential to prevent the liver from storing large amounts of
fat [ 43]. By inducing mitochondrial, peroxisomal, and
microsomal fatty acid oxidation, PPAR α reduces hepatic fat
accumulation in the liver during the development of fatty liver
disease, and thus prevents steatosis [ 31, 44, 45]. It can be
hypothesized that since PPAR α has a potent
anti-inflammatory activity in liver, the progression of steatosis
towards steatohepatitis might be counteracted by PPAR α.
Indeed, several studies in mice have shown that PPAR α
activation is able to reduce or even reverse steatohepatitis
induced by feeding a methionine- and choline-deficient (MCD)
diets [ 31, 45, 46]. In a mouse model of steatohepatitis, the presence and activation
of PPAR α prevented the induction of COX-2 expression
[ 47]. Since upregulation of COX-2 is seen in alcoholic
steatohepatitis and nonalcoholic steatohepatitis and has been
directly linked to the progression of steatosis to
steatohepatitis, the inhibitory effect of PPAR α on COX-2
may reduce steatohepatitis. An anti-inflammatory role of
PPAR α in the development of steatohepatitis is further
supported by a study in which wild-type and PPAR α −/−
mice were fed a high-fat diet to induce obesity. Although both
genotypes developed a fatty liver after chronic high-fat feeding,
animals lacking PPAR α developed steatohepatitis
accompanied by an increased number of infiltrated lymphocytes and
macrophages. By suppressing the expression of specific chemokines
involved in attracting macrophages and other immune-related cell
types, PPAR α might moderate steatohepatitis
[Stienstra et al., submitted]. These results are in line
with a study performed in APOE2 knock-in mice fed a western-type
high-fat diet [ 48]. When the animals were cotreated with fenofibrate, macrophage infiltration of the liver was prevented. 2.2. PPARα and atherosclerosis Inflammation in the arterial wall is known to promote the process
of atherosclerosis [ 49]. In addition to suppressing the inflammatory response in liver, PPAR α may also influence
inflammatory reactions in the arterial wall. As PPAR α is
expressed in various cell types present in atherosclerotic
lesions, the effect of PPAR α on lesion development is
rather complex. Immune-modulating effects of specific PPAR α
activation have been reported in various cell types. However, some
controversy still exists about the exact role of PPAR α in
the vascular wall as both pro- and antiatherogenic effects of
PPAR α have been demonstrated. An antiatherogenic effect of PPAR α via suppression of
several proinflammatory genes like MCP-1, TNF α, vascular
cell adhesion molecule-I (VCAM I), intercellular adhesion
molecule-I (ICAM I), and interferon- γ (IFN γ) has
been reported in the vascular wall of animals with extensive
atherosclerosis [ 50]. Other studies have shown that the anti-inflammatory role of PPAR α in the vascular wall seems
to be dependent on the severity of inflammation or vascular
lesion. In the absence of inflammation or in early lesions, the
effects of PPAR α are mainly proatherogenic [ 51, 52],
whereas the development of severe lesions accompanied by
inflammation is strongly reduced by PPAR α
activation. Several acute phase proteins have been linked to the development
of atherosclerosis [ 53]. This includes CRP, which is
currently used as a marker for systemic inflammation and linked to
CVD, and serum amyloid A (SAA), which has been shown to be
involved in the development of atherosclerosis [ 54]. As PPAR α activation downregulates plasma concentrations of
acute phase proteins including CRP and SAA in humans [ 42], it might indirectly prevent or slow down the progression of
atherosclerosis. 2.3. PPARα and adiposity Although expression of PPAR α in WAT is much lower compared
to PPAR γ, evidence abounds that PPAR α may also
influence adipose tissue function. It has been shown that
PPAR α −/− mice gain more adipose mass compared to
wild-type animals [ 55], which may be via local or systemic effects of PPAR α. An antiobesity role for PPAR α is
supported by several studies in which obese rodents were
administered synthetic PPAR α agonists [ 56– 58].
While it is true that PPAR α agonists have a clear anorexic
effect resulting in decreased food intake, evidence is
accumulating that PPAR α may also directly influence
adipose tissue function, including its inflammatory
status. A recent study revealed that treatment of obese diabetic KKAy mice
with Wy-14643 decreased adipocyte hypertrophy as well as
macrophage infiltration [ 59]. In PPAR α −/− mice
chronically fed a high-fat diet (HFD), expression of inflammatory
genes in adipose tissue was more pronounced compared to wild-type
mice. In addition, fractionation of adipose tissue in adipocytes
and stromal vascular cells revealed higher gene expression levels
of the specific macrophage marker F4/80+ in the stromal vascular
fraction of PPAR α −/− mice [Stienstra
et al., submitted]. PPAR α may govern adipose tissue inflammation in three
different ways: (1) by decreasing adipocyte hypertrophy, which is
known to be connected with a higher inflammatory status of the
tissue [ 3, 11, 59], (2) by direct regulation of inflammatory
gene expression via locally expressed PPAR α, or (3) by
systemic events likely originating from liver. Full clarification
of the role of locally expressed PPAR α in adipose tissue
will have to await the availability of adipose tissue-specific
PPAR α −/− mice. Thus, while evidence is mounting that PPARα activation
reduces adipose inflammation as observed during obesity, it is
unclear whether the anti-inflammatory effects of PPARα in
WAT are caused by direct or indirect mechanisms. Compared to PPAR α and PPAR γ, much less is known
about PPAR β/ δ and its natural ligands. Due to its
ubiquitous expression profile, lack of specific ligands
and, until recently, lack of availability of knock-out models, the
role of PPAR β/ δ in many tissues has been poorly
explored. Fortunately, the recent generation of PPAR β/ δ
−/− mice has provided a strong impetus for the characterization
of the function of PPAR β/ δ [ 60]. Several abnormalities have been observed in mice lacking PPAR β/ δ which include impaired wound healing, a decrease in adipose
mass, and disturbed inflammatory reactions in skin [ 61]. PPAR β/ δ has been directly linked to the
development of obesity. Indeed, several groups have reported a
decrease in adiposity after PPAR β/ δ activation. By
stimulating fatty acid oxidation, PPAR β/ δ activation
leads to loss of adipose mass in different mouse models of obesity
[ 62]. Similar effects on fatty acid oxidation have been
observed in heart, resulting in improved muscle contraction
[ 63]. In addition to increasing fatty acid oxidation,
activation of PPAR β/ δ in muscle also increases the
number of type I muscle fibers, which leads to enhanced endurance
performance [ 64]. The number of studies that have addressed the role of PPAR β/ δ during inflammation is limited. So far, an
anti-inflammatory effect has been observed in macrophages
suggesting a possible role for PPAR β/ δ in the process
of atherogenic inflammation. It appears that PPAR β/ δ
acts as an inflammatory switch in which inactivated
PPAR β/ δ is proinflammatory and activated
PPAR β/ δ promotes an anti-inflammatory gene expression
profile. The proposed switch of PPAR β/ δ is linked to
the B cell lymphoma-6 (BCL-6) protein which functions as
inflammatory suppressor protein [ 65]. In the unliganded state, BCL-6 is part of the PPAR β/ δ-RXR α
transcriptional complex. Upon ligand activation, corepressors
including BCL-6 are dissociated and PPAR β/ δ-dependent
gene transcription ensues. The released BCL-6 subsequently acts as
a repressor of proinflammatory gene expression in macrophages. 3.1. PPARβ/δ and steatosis It can be hypothesized that the stimulatory effect of PPAR β/ δ on fatty acid oxidation in muscle and adipose tissue
might also extend to liver, which would render PPAR β/ δ an antisteatotic role in liver. Within the liver, PPAR β/ δ expression is found in different cell types although the highest levels are found in hepatic endothelial cells [ 66]. According to a recent report by Nagasawa et al., activation of
PPAR β/ δ may diminish fatty liver disease. In this
study, mice were fed an MCD diet to induce steatohepatitis.
Administration of the PPAR β/ δ agonist {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981"}}GW501516 not
only decreased hepatic lipid content, yet it also reduced
inflammatory gene expression. PPAR β/ δ decreased fat
storage in liver mainly by activation of genes involved in fatty
acid oxidation. Furthermore, the elevated mRNA levels of
transforming growth factor- β1 (TGF- β1), TNF α,
MCP-1 and interleukin-1 β (IL-1 β) that accompany the
development of steatohepatitis were counteracted by
PPAR β/ δ activation [ 67]. Which liver cell types and molecular mechanisms contribute to the observed regulation is
unknown. 3.2. PPARβ/δ and atherosclerosis Due to the anti-inflammatory properties of PPAR β/ δ in
macrophages, it is plausible that atherosclerosis is affected by
PPAR β/ δ-activation. By feeding low-density lipoprotein
receptor (LDLR) −/− mice a hypercholesterolemic diet
supplemented with a specific PPAR β/ δ ligand, it was
shown that PPAR β/ δ is able to interfere with the
inflammatory process underlying the development of
atherosclerosis. Whereas lesion development itself was not
prevented by PPAR β/ δ activation, inflammatory gene
expression was blunted compared to untreated mice [ 50]. The anti-inflammatory action of PPAR β/ δ was mainly achieved by a strong inhibition of VCAM-1,
MCP-1, and IFN- γ expressions, genes that are
associated with the development of atherosclerosis. A recent study
in which LDLR −/− mice were treated with the PPAR β/ δ agonist GW0742X revealed an antiatherosclerotic effect of
PPAR β/ δ, in addition to an anti-inflammatory effect.
Lesion development was strongly inhibited and inflammatory gene
expression in macrophages was decreased [ 68]. While in mice there is compelling evidence for an
anti-inflammatory role of PPAR β/ δ in the
atherosclerosis, the role of PPAR β/ δ in humans is
relatively unknown. Remarkably, PPAR β/ δ was shown to
strongly promote lipid accumulation in human macrophages, thereby
supporting the development of atherosclerosis [ 69]. Whether PPAR β/ δ influences inflammatory gene expression in
human cells needs further study. 3.3. PPARβ/δ and adiposity Recently, it was shown that activation of PPAR β/ δ in
adipose tissue causes a marked decrease in fat mass which is
mainly achieved by activation of fatty acid oxidative pathways
[ 62]. Moreover, high-fat-diet-induced adiposity was strongly
inhibited by activation of PPAR β/ δ in adipose tissue.
Whether PPAR β/ δ is able to control inflammatory gene
expression in WAT during diet-induced obesity is still unclear.
Inasmuch as inflammatory gene expression is linked to adiposity,
it could be hypothesized that inflammatory gene expression will be
suppressed by PPAR β/ δ activation. Also, since
expressions of IL-1 β, MCP-1, and TNF α are
controlled by PPAR β/ δ in liver [ 67], it is tempting to speculate that inflammatory gene expression is under
control of PPAR β/ δ in adipose tissue as well. PPAR γ is considered the master regulator of adipogenesis,
and accordingly has been extensively studied in the context of
obesity. In humans, PPAR γ is most highly expressed in
adipose tissue, yet reasonable levels of PPAR γ mRNA can
also be found in other organs including skeletal muscle, colon,
and especially lung [ 70]. The latter is probably due to the abundance of macrophages in lung. At least two different isoforms
of PPAR γ are known: PPAR γ1, which is the form
expressed in nonadipose tissues, and PPAR γ2, which is
adipose-tissue specific. Unsaturated fatty acids and several
eicosanoids serve as endogenous agonists of PPAR γ, while
antidiabetic drugs belonging to the thiazolidinediones act as
synthetic agonists of PPAR γ. Target genes of PPAR γ
are involved in adipocyte differentiation, lipid storage, and
glucose metabolism, and include lipoprotein lipase, CD36,
phosphoenolpyruvate carboxykinase, aquaporin 7, and adiponectin
[ 71]. Gain and loss of function studies have shed more light on the
specific functions of PPAR γ in different tissues. While
homozygous PPAR γ-deficient animals are embryonically
lethal, specific ablation in adipose tissue revealed the
indispensable role of PPAR γ in adipocyte differentiation
and function [ 72]. In liver, PPAR γ is involved in triglyceride homeostasis and contributes to steatosis. At the same
time, hepatic PPAR γ protects other tissues from
triglyceride accumulation and insulin resistance [ 73]. Similar to PPAR α, PPAR γ is involved in governing
the inflammatory response, especially in macrophages. Currently,
two different molecular mechanisms have been proposed by which
anti-inflammatory actions of PPAR γ are effectuated: (1)
via interference with proinflammatory transcription factors
including STAT, NF- κB, and AP-1 [ 74], and (2) by preventing removal of corepressor complexes from gene promoter
regions resulting in suppression of inflammatory gene
transcription [ 75]. This mechanism involves ligand-dependent SUMOylation of PPAR γ followed by binding of PPAR γ
to nuclear receptor corepressor (NCoR)-histone deacetylase-3
(HDAC3) complexes localized on inflammatory gene promoters. The
binding of PPAR γ prevents the removal of corepressor
complexes, thus retaining inflammatory genes in a suppressed
state. 4.1. PPARγ and adiposity PPAR γ is indispensable for adipocyte differentiation both
in vivo and in vitro [ 76– 78]. In spite of its vital role
in adipogenesis and lipogenesis, PPAR γ expression itself
is not strongly influenced during obesity. As discussed above,
diet-induced obesity is associated with increased inflammatory
gene expression in adipose tissue via adipocyte hypertrophy and
macrophage infiltration. It has been shown that PPAR γ is
able to reverse macrophage infiltration, and subsequently reduces
inflammatory gene expression [ 18]. Adipose expression of
inflammatory markers A disintegrin and metallopeptidase domain-8
(ADAM8), macrophage inflammatory protein-1 α
(MIP-1 α), macrophage antigen-1 (MAC-1), F4/80+, and
CD68 was downregulated by specific PPAR γ activation.
Inflammatory adipokines mainly originate from macrophages which
are part of the stromal vascular fraction of adipose tissue
[ 18, 19], and accordingly, the downregulation of inflammatory
adipokines in WAT by PPAR γ probably occurs via effects on
macrophages. By interfering with NF- κB signaling pathways,
PPAR γ is known to decrease inflammation in activated
macrophages [ 74]. PPAR γ may also influence inflammatory gene expression via effects on adipocyte morphology.
Indeed, smaller adipocytes are known to secrete less inflammatory
markers compared to larger adipocytes [ 3]. Treatment of obese rats with the synthetic PPAR γ agonist troglitazone
dramatically reduced the size of adipocytes without changing the
total weight of WAT. In parallel, the expression levels of the
inflammatory marker TNF α were normalized compared to those
of untreated rats [ 79]. Furthermore, by inducing the
expression of adiponectin in adipocytes [ 80], PPAR γ may directly contribute to suppression of chronic inflammation
accompanying obesity. Summarizing, the anti-inflammatory effects of PPAR γ
activation in adipose tissue are presumably achieved by effects on
both adipocytes and adipose tissue-resident macrophages.
Interestingly, PPAR γ is induced both during macrophage and
adipocyte differentiation [ 71]. Since preadipocytes that are present in adipose tissue have the ability to differentiate
towards macrophage-type cells and towards adipocytes depending on
the local environment [ 81], the role of PPAR γ in
determining the fate of preadipocytes is of interest. It can be
hypothesized that activation of PPAR γ might favor
adipocyte differentiation resulting in a decreased inflammatory
status of adipose tissue during obesity. 4.2. PPARγ and atheroslerosis PPAR γ is expressed in white blood cells and differentiated
macrophages and has been implicated in the process of
atherosclerosis. Initially, PPAR γ activation was proposed
to be proatherogenic by stimulating uptake and storage of oxidized
lipids in macrophages via upregulation of the scavenger
receptor/fatty acid transporter CD36. This process leads to foam
cell development and is a key event in the development of
atherosclerosis [ 82]. In contrast, treatment with
thiazolidinediones has been shown to reduce the development of
atherosclerosis in mouse models [ 50, 71], suggesting that
PPAR γ is antiatherogenic. The inhibitory effect on
atherosclerosis may be mediated by upregulating expression of the
ABCA1 transporter in macrophages, thereby promoting cholesterol
efflux. Furthermore, PPAR γ activation strongly reduces
inflammatory gene expression in macrophages, including MCP-1,
VCAM-1, ICAM-1, IFN γ, and TNF α [ 50]. Several human studies also point to antiatherogenic effects of PPAR γ in type II diabetic patients. Daily administration of 400 mg troglitazone or 30 mg pioglitazone for 6 months resulted in a reduction of common carotid arterial intimal and medial complex
thickness which is used as a noninvasive method to monitor early
atherosclerotic lesions [ 83, 84]. In a randomized controlled
trial using 5238 patients with type II diabetes, treatment with
15 mg to 45 mg pioglitazone improved cardiovascular
outcome [ 85]. Whether these protective effects in humans are achieved by inhibiting inflammation remains to be determined. 4.3. PPARγ and steatosis It has been well established that in mouse models of steatosis,
the development of fatty liver is associated with increased
hepatic expression of PPAR γ. In a nonfatty liver, the role
of PPAR γ appears to be limited and is probably restricted
to stellate cell function during liver injury-induced fibrogenesis
[ 86]. During the development of steatosis, hepatocytes become lipid-loaden and gain phenotypical characteristics of
adipocytes which include the formation of large lipid droplets. In
parallel, expression of adipogenic and lipogenic genes such as
sterol regulatory element binding protein (SREBP), Adipose
differentiation-related protein (ADRP) and PPAR γ
are strongly upregulated in steatotic livers
[ 87, 88]. Likely, the upregulation of PPAR γ
contributes to the phenotype, since adenoviral-mediated hepatic
overexpression of PPAR γ1 on a PPAR α −/−
background dramatically increases hepatic lipid accumulation and
adipogenic gene expression in mice [ 89]. Also, marked upregulation of PPAR γ in livers of PPAR α −/− mice
fed a high-fat diet leads to increased expression of adipocyte
markers and might contribute to the fatty liver phenotype
[ 43]. In contrast, mice that specifically lack PPAR γ in liver are protected from hepatic steatosis and show decreased
expression levels of lipogenic genes compared to wild-type mice
[ 73, 90]. Thus, PPAR γ induction appears to be
necessary and sufficient for hepatic steatosis. The development of steatosis and progression into steatohepatitis
is closely linked to an increased inflammatory state of the liver
[ 4]. Recent data suggest that activation of PPAR γ in
fatty liver may protect against inflammation. Microarray analysis
revealed that several inflammatory genes that are upregulated in
fatty livers of mice fed a high-fat diet were strongly
downregulated by PPAR γ overexpression in liver [ 89]. These genes include SAA, Chemokine (C-X-C motif) ligand 10
(CXL10)/IP10 and interferon- γ-inducible protein,
47 kd. Data from our own group showed that hepatic PPAR γ activation by rosiglitazone under steatotic conditions results
in downregulation of multiple proinflammatory genes. Thus,
although activation of PPAR γ in liver contributes to the
development of steatosis, inflammatory gene expression is
suppressed. Several small clinical human studies have been performed to
evaluate the effects of thiazolidinediones in patients diagnosed
with NASH. After treatment, the degree of steatosis and
inflammation improved in a number of patients indicating that
PPAR γ may be an interesting pharmacological target
[ 91]. Apart from weight gain, no side effects were reported
in these studies. However, more studies are needed to assess the
potentially beneficial effects of PPAR γ activation on
liver function. An elevated inflammatory status is increasingly believed to be an
important mediator that links excess (visceral) fat mass with
numerous metabolic abnormalities, including insulin resistance.
PPARs may influence the inflammatory response either by direct
transcriptional downregulation of proinflammatory genes via
mechanisms involving transrepression, or indirectly via their
transcriptional effects on lipid metabolism. Numerous animal
studies have demonstrated a role for PPARs in counteracting
obesity-induced inflammation in liver, adipose tissue, and the
vascular wall. The ability to reduce inflammatory cell
infiltration further underlines the central role of PPARs in
obesity-induced inflammation (). A growing number of studies strongly support anti-inflammatory
properties of PPARs in human obesity as well. Several clinical
trials in type II diabetic or hyperlipidemic patients have clearly
shown that PPAR α agonists including fenofibrate,
ciprofibrate, and gemfibrozil can effectively reduce circulating
levels of TNF α, IL-6, fibrinogen, and CRP [ 92]. Rosiglitazone, a selective PPAR γ agonist, exerts
anti-inflammatory effects in both obese and type II
diabetic individuals by decreasing plasma
concentrations of C-reactive protein, serum amyloid-A, and matrix
metalloproteinase [ 93, 94]. Since synthetic PPARα and PPARγ agonists
independently ameliorate obesity-induced inflammation, agonists
that activate both PPARα and PPARγ (the so-called
dual PPARα/PPARγ agonists) might be even more
effective. Unfortunately, the development and clinical trials of
these compounds have been hampered by serious concerns regarding
their safety. Many dual PPARα/PPARγ agonists once
in clinical development have since been abandoned, often for
reasons of toxicity, including most recently the dual agonist
tesaglitazar. In conclusion, although more work is needed to evaluate their full
potential in humans, especially in terms of safety, PPAR agonists
nevertheless represent a promising strategy to mitigate
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