vie
or-
abo
ti, S
r, R
er, 11
d form
to human adipogenesis, insulin sensitization, lipid
thrombotic state to perhaps provide justification for
c targ
syndrome, metab
drome, refers to a
factors [1–5]. Pa
increased risk for
uals, the prevalence of metabolic syndrome is approximately
of metabolic risk
demia, hyperten-
receptors (PPARs) are regulators of numerous metabolic
dicinincrease. Although metabolic syndrome has been variably
defined in the past, the National Cholesterol Education
Program (NCEP) Adult Treatment Panel (ATP) III guide-
lines state that individuals with any three of the following
five abnormalities can be classified as having metabolic
syndrome: abdominal obesity, atherogenic dyslipidemia,
hypertension, insulin resistance and prothrombotic state
[11]. There is high degree of association of the individual
components of metabolic syndrome with cardiovascular
risk, and several recent analyses have shown that the cluster
pathways has led to a huge increase in the development and
use of agonists of these receptors as therapeutics for
diabetes, dyslipidemia and atherosclerosis [14]. PPARs are
members of the nuclear receptor family that includes steroid
and thyroid hormones [15] and consist of a group of three
isoforms: PPARa, PPARh/y and PPARg. The best charac-
terized action of PPARa is to mediate the uptake and h-
oxidation of fatty acids in various tissues including the liver
and heart [16,17], whereas PPARg is best known for its
ability to promote preadipocyte differentiation, to mediateage, the prevalence rate of metabolic syndrome continues to
50%, and as the population of the United States continues to The recognition that peroxisome proliferator-activatedvascular disease [6–9]. Approximately 23.7% of the U.S.
population have metabolic syndrome [10]. In older individ- 2. Peroxisome proliferator-activated receptorsof risk factors in
increased risk of
[7,11,12]. The r
1522-1865/04/$ – see
doi:10.1016/j.carrad.2
* Corresponding a
E-mail address: roolic syndrome x, and dismetabolic syn-
specific clustering of cardiovascular risk
tients with metabolic syndrome are at an
the development of diabetes and cardio-
reversals of root causes and direct therapy
factors including insulin resistance, dyslipi
sion and prothrombotic state [8].1. Metabolic syndrome
Metabolic syndrome, also known as insulin resistance
obesity and physical inactivity, and metabolic syndrome is
closely associated with insulin resistance [11,13]. Treatment
of metabolic syndrome consists primarily of two strategies:Re
Peroxisome proliferat
Its role in met
Rajbabu Pakala, Pramod Kuchulakan
Richard Baffou
Cardiovascular Research Institute, Washington Hospital Cent
Received 22 March 2004; received in revise
Abstract Here we review PPARg function in relation
metabolism, blood pressure regulation and pro
this nuclear receptor remaining a key therapeuti
treat human metabolic syndrome.
D 2004 Elsevier Inc. All rights reserved.
Keywords: Metabolic syndrome; Diabetes mellitus
Cardiovascular Radiation Memetabolic syndrome is associated with
cardiovascular morbidity and mortality
oot causes of metabolic syndrome are
front matter D 2004 Elsevier Inc. All rights reserved.
004.03.006
uthor. Tel.: +1-202-877-8575; fax: +1-202-877-2715.
n.waksman@medstar.net (R. Waksman).et for the continuing development of agents tow
activated receptor g:
lic syndrome
eung-Woon Rha, Edouard Cheneau,
on Waksman*
0 Irving Street NW, Suite 4B-1, Washington, DC 20010, USA
25 March 2004; accepted 25 March 2004
e 5 (2004) 97–103lipogenesis in adipocytes and to enhance insulin sensitivity
[15,18]. PPARh/y is best known for its role in skin homeo-
stasis, and has recently been shown to play a role in high-
density lipoprotein (HDL) metabolism [15,17].
Like other nuclear receptors, PPARg has a modular
structure consisting of a DNA-binding domain and a

and that the presence of PPARg agonists is sufficient for
insulin resistance being evident even in early childhood
Radiadipogenesis [29,32]. PPARg is essential for placental
adipose tissue development [33] and heterozygous PPARg
null mice have reduced adipose tissue depots [34]. As in
rodents, in humans PPARg is also highly expressed in
adipose tissue [35], and exposure of cultured primary
human preadipocytes to PPARg agonists such as rosiglita-
zone and pioglitazone (TZDs) induces their differentiation
[36]. Treatment with TZDs promotes weight gain in
humans, which may be a result of improved insulin sensi-
tivity; however, it is possible that lowering circulating
insulin levels by itself can actually diminish its anabolic
activity. An alternative and more possible hypothesis is that
PPARg agonists improve insulin sensitivity by promoting
adipogenesis and postprandial fatty acid/triglyceride storage
within adipocytes, both of which are likely to increase
adipose tissue mass. Several studies have shown that the
increase in body weight associated with TZD treatment is
mediated principally by accumulation of subcutaneous (SC)
fat, whereas visceral adipose tissue is unchanged or reduced.
These observations are in keeping with ex vivo studies in
which preadipocytes isolated from SC abdominal adipose
tissue differentiated more readily in response to TZDs than
cells from visceral depots of the same subjects [36,37]. It isligand-binding domain (LBD). Many of its biological
effects are mediated by receptor regulation of target gene
transcription in a ligand-dependent manner. Dimerization
of PPARg with a retinoid X receptor (RXR) forms a
heterodimer, which upon binding with a cognate or exoge-
nous ligand promotes activation of gene transcription.
Endogenous ligands of PPARg include polyunsaturated
fatty acids (e.g., linoleic acid and arachidonic acid), 15-
deoxy D12,14 prostaglandin J2 and eicosanoids [e.g.,
hydroxyoctadecadienoic acid (HODE) and hydroxyeicosa-
tetraenoic acid] [19–21]. The first synthetic compound
reported as a high-affinity PPARg agonist was thiazolidi-
nediones (TGDs) or glitazones class of antidiabetic agent
[22,23]. (S)-Enantiomers of TGDs were shown to have
higher affinity than the (R)-enantiomers [24]. Recently, a
series of L-tyrosine-based PPARg agonists that were
shown to have greater binding affinity and functional
activity was synthesized [25,26]. In addition to these
potent PPARg ligands, a subset of nonsteroidal anti-
inflammatory drugs (NSAIDs), including indomethacin,
fenoprofen and ibuprofen have been shown to display
weak PPARg activity [27].
3. PPARg and adipogenesis
PPARg is the foremost regulator of adipogenesis [28,29].
It is highly expressed in adipose tissue [30], with induced
expression early in the preadipocyte differentiation [31].
Studies modulating PPARg expression or action in rodent
cell lines have confirmed both that the receptor is essential
R. Pakala et al. / Cardiovascular98not known whether TZD treatment increases SC fat mass in[50]. Metabolic studies of these subjects have enlightened
mechanisms by which PPARg dysfunction might lead to
insulin resistance [51]. Adipose tissue is also an important
source of hormones, collectively referred to as adipokines:
leptin [52], adiponectin [53], tumor necrosis factor a
(TNFa) [54], and resistin [55], which have been shown
to regulate insulin-mediated glucose disposal. For example,
circulating adiponectin levels have been shown to correlate
closely with insulin sensitivity and inversely with that of
fat mass [56–58]. Thiazolidinediones have been shown to
increase adiponectin gene expression, suggesting that this
adipokine may be a critical link between PPARg activation
and insulin sensitization [59,60]. Interestingly, circulating
adiponectin levels were found to be dramatically lower inall body regions; this question is of particular interest
because there is increasing evidence to suggest that there
are important functional metabolic differences between
upper body (abdominal) and lower body SC fat [38].
Selective loss of limb and gluteal fat is observed in
subjects with loss-of-function mutations within the LBD
of human PPARg. In animal studies, PPARg agonists alter
adipose tissue morphology dramatically with apoptosis of
old, hypertrophic adipocytes and differentiation of smaller
insulin-sensitive adipocytes [39], but no information is
available on human adipocyte. Taken together, these obser-
vations support the notion that PPARg is a critical regu-
lator of human adipose tissue mass.
4. PPARg and insulin sensitivity
Studies of TZDs, a novel class of agents developed for
the treatment of type 2 diabetes mellitus (T2DM), have
provided critical evidence for the role of PPARg in insulin
sensitivity [22,23]. Though synthesized as hypolipidemic
derivatives of clofibrate, TZDs were shown to control
blood glucose by their insulin-sensitizing actions in animal
models of T2DM and in humans [40]. Lehmann et al. [41]
have shown that TZDs are selective high-affinity ligands
for PPARg, with the rank order of their potency for
receptor activation in vitro closely correlating with their
glucose-lowering activity in vivo [42,43]. Recently, selec-
tive non-TZD PPARg ligands (i.e., tyrosine-based agonists)
have been shown to exert potent antidiabetic effects in
preclinical studies and early clinical trials [44,45], provid-
ing additional evidence for the role of PPARg in insulin
sensitivity. Compounds that activate RXR (the heterodi-
meric partner for PPARg) have also been shown to
improve in vivo insulin sensitivity in animal models [46].
Studies on human PPARg genetic variants have shown
further evidence that PPARg is a critical regulator of
insulin action in man. In patients with loss-of-function
PPARg mutations, severe insulin resistance (with or with-
out evident T2DM) is a consistent finding [47–49], with
ation Medicine 5 (2004) 97–103individuals who have loss-of-function PPARg mutations