bLabora
Abstract
The deve
diabetes mel
hypertriglyc
PPAR
agon
role of PPAR
in skeletal m
It seems that
of PPAR
m
metabolic sy
of PPAR
it
? 2006 Elsevi
Keywords: PP
The pre
oped count
so-called m
associated
and overt d
diseases at
global epid
completely
and change
Metabo
hyperglyce
demia and
the Nation
Detection,
terol in Ad
that approx
syndrome
∗
Correspon
E-mail ad
1043-6618/$
doi:10.1016/jPharmacological Research 53 (2006) 501–507
Peroxisome proliferator-activated receptor
(PPAR
),anovel
target site for drug discovery in metabolic syndrome
Sadao Takahashi
a
, Toshiya Tanaka
b
, Tatsuhiko Kodama
b
, Juro Sakai
b,c,∗
a
Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-0063, Japan
tory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 153-8904, Japan
c
Exploratory Research for Advanced Technology of Japan Science and Technology Corporation, Aomi 153-0064, Japan
lopment of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and
litus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR) and  agonists have shed light on the treatment of
eridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPAR
functions is lagging behind because specific
ists have not been developed. The appearance of new PPAR
agonists is brightening the prospects for elucidating the physiological

.PPAR
is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation
uscle and adipose tissue by PPAR
agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough.
treatment of PPAR
agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role
ay be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPAR
agonists against
ndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions
self and its agonists in the future.
er Ltd. All rights reserved.AR
; Metabolic syndrome; Fatty acids oxidation; Adaptive thermogenesis
valence of obesity has risen dramatically in devel-
ries. This phenomenon has led to an increase in the
etabolic syndrome. Because metabolic syndrome is
with increased risk of coronary heart disease (CHD)
iabetes, it is important to prevent progress of serious
an early stage. Although the precise reason for the
emic of obesity and metabolic syndrome has not been
elucidated, it is accepted that environmental factors
s in life style are major contributors.
lic syndrome is composed of abdominal obesity,
mia due to insulin resistance, atherogenic dyslipi-
hypertension [1]. Based on the Third Report of
al Cholesterol Education Program Expert Panel on
Evaluation, and Treatment of High Blood Choles-
ults (Adult Treatment Panel III), it has been reported
imately 22% of adults in the USA have metabolic
[2]. Furthermore based on data from the Third
ding author. Tel.: +81 3 5452 5472.
dress: jmsakai@med.rcast.u-tokyo.ac.jp (J. Sakai).
National H
III), Ninom
metabolic s
stroke, and
metabolic
is at a sub
the major p
numerous r
nisms of m
Among
(PPARs) a
approaches
PPARs are
fatty acid
superfamil
erodimers b
is a direct
3) half-site
genes. Thr
this review
sue distribu
– see front matter ? 2006 Elsevier Ltd. All rights reserved.
.phrs.2006.03.019ealth and Nutrition Examination Survey (NHANES
iya et al. [3] have evaluated the association between
yndrome and history of myocardial infarction and/or
have given a definite opinion that the presence of
syndrome identifies a cohort of the population that
stantial risk of cardiovascular disease. To address
ublic health concerns faced by developed countries,
esearches have emerged for elucidating the mecha-
etabolic syndrome.
them, peroxisome proliferator-activated receptors
gonists have shed light on effective therapeutic
for correcting some aspects of metabolic syndrome.
ligand-activated transcription factors that control
metabolism, and members of the nuclear receptor
y. Together with retinoid X receptors (RXRs), the het-
ind to the PPAR-responsive element (PPRE), which
repeat of two similar hexanucleotide (5-AGGTCA-
s separated by one or two nucleotides on its target
ee subtypes, PPAR,PPAR/
(refer to PPAR
in
), and PPAR have been identified with distinct tis-
tion and biological activities [4]. The roles of PPAR

502 rch 53
and PPAR
their agoni
that is prim
liver, and t
heart, binds
ing leukotr
acid (8S-H
enhanced a
sufferings
gests that P
oxidation i
is highly ri
adipocyte d
sis. The in
are selectiv
postprandia
eral establi
detail [4,7]
with a less
been obtain
activators,
progress. In
dated funct
1. Tissue d
Schmid
steroid hor
defined as
PPAR
is e
the three P
mRNA lev
kidney by u
PPAR ex
tine, and P
tissues in t
(PGI
2
), car
PPAR
lig
GlaxoSmit
GW501516
over other
low-density
endogenou
in VLDL t
efficient ac
macrophag
cles. Those
lipoprotein
sion of the
liver X rec
differentiat
induce CD
2. Homoz
Two ho
lished. Gon
g the
PAR
o the
in br
mRN
has
ted t
brain
hile
gen
re p
rvive
n tw
targe
retai
ted th
l mic
thal
ipoc
R
exp
ts th
mig
-worS. Takahashi et al. / Pharmacological Resea
in particular have been exclusively studied because
sts have been used in the clinical market. PPAR
arily expressed in brown adipose tissue (BAT) and
o a lesser extent in the kidney, skeletal muscle, and
to hypolipidemic fibrates and natural ligands includ-
iene B4 (LTB4) and 8-(S)-hydroxyeicosatetraenoic
ETE). Fasted PPAR−/− (knockout) mice show
ccumulation of lipid in the liver and heart due to
from severe hypoglycemia and hypothermia. It sug-
PAR plays a crucial role in fatty acid uptake and
n the liver and heart [5,6]. On the other hand, PPAR
ch in adipocytes and macrophages, and is involved in
ifferentiation, lipid storage, and glucose homeosta-
sulin-sensitizing thiazolidinediones (TZDs), which
e ligands of PPAR consistently lower fasting and
l glucose levels as well as free fatty acid levels. Sev-
shed mechanisms for TZDs have been reviewed in
. To the contrary, PPAR
is expressed ubiquitously
defined function because selective agonists have not
ed. However, the development of selective PPAR

has allowed investigations on the functions of PPAR

this review, we focus mainly on the recently eluci-
ions of PPAR
.
istribution and ligands of PPAR

lackin
[11].P
stage t
losum
CD 36
dermis
sugges
in the
Meanw
PPAR

mice a
that su
betwee
ferent
might
indica
no nul
of a le
3. Ad
PPA
forced
conver
PPAR

and cot et al. [8] first discovered a novel member of the
mone receptor superfamily cDNA as NUC1 (later on
PPAR/
) from a human osteosarcoma cell library.
xpressed ubiquitously and is the most abundant of
PARs in most tissues except adipose tissue. PPAR

els are dramatically down-regulated in the liver and
p to 80% after an overnight fast. On the other hand,
pression is up-regulated in the liver and small intes-
PAR expression is decreased by 50% in adipose
he fasted state in mature rat tissues [9]. Prostacyclin
baprostacyclin (cPGI
2
), and saturated fatty acids are
ands, but those ligands also activate PPAR or .
hKline first identified a high-affinity PPAR
ligand,
that has more than 1000-fold selectivity for PPAR

subtypes. Chawla et al. [10] reported that native very
lipoprotein (VLDL) particles may be one of the
s sources of PPAR
ligands. Especially triglycerides
hat is hydrolyzed by lipoprotein lipase (LPL) are an
tivator of PPAR
in macrophages. PPAR
deficient
es lost the transcriptional response by VLDL parti-
findings are interest because oxidized low-density
(ox-LDL) activates PPAR and induce the expres-
scavenger receptor, CD36 and the oxysterol receptor,
eptor (LXR). PPAR
activation induces adipose
ion-related protein (ADRP) expression but does not
36 or LXR.
ygous PPAR
knockout mice
mozygous PPAR
−/− mice lines have been estab-
zalez and colleagues established PPAR
−/− mice
3T3C2 fibr
ferentiation
or PPAR
exposure o
nist promo
They sugge
trol of PPA
that overex
adipose-rel
cells. A tr
the AF2 do
PPAR
pla
tion of prea
synergistic
enhances th
is only mod
plays a role
impact of P
dent on var
PPAR ma
in vitro stu
adipose tiss
pose tissue
leanness bu
and no eff
L1 cells is
the direct e
tissue in v
tions in sys
adipocyte d
mice.(2006) 501–507
ligand-binding domain of the murine PPAR
gene

−/− mice are smaller than normal from the fetal
postnatal period and myelination of the corpus cal-
ain is altered. Gonadal adipose stores are smaller and
A levels are higher. Enhanced hyperplasia of the epi-
been detected in the skin of PPAR
−/− mice. They
hat PPAR
is involved in development, myelination
, lipid metabolism, and epidermal cell proliferation.
Barak et al. [12] also eliminated almost the entire
e in mice. Over 90% of the embryos PPAR
−/−
rone to die due to placental defects and the mice
show an extremely lean phenotype. The difference
o knockout mice for lethality is likely due to the dif-
ting strategies. The former truncated receptor mice
n PPAR activity for survival. Michalik et al. [13] also
at only few PPAR
−/− mice could be obtained but
e line could be established for very high penetrance
phenotype.
yte differentiation
is induced during adipocyte differentiation, and a
ression of PPAR in nonadipogenic cells effectively
em to mature adipocytes. Like PPAR, it seems that
ht be involved in adipocyte differentiation. Grimaldi
kers [14] created the forced PPAR
expressing Swissoblasts, which are normally refractory to adipose dif-
. They found that a treatment of fatty acids alone
agonist is not sufficient to trigger adipogenesis but
f cells to a combination of fatty acids and PPAR ago-
tes the expression of a typical adipose differentiation.
sted that PPAR gene expression is under the con-
R
activated by fatty acids. Furthermore they showed
pression of PPAR
enhances fatty acid induction of
ated genes in Ob1771 and 3T3-F442A preadipocyte
ansactivation-deficient form of PPAR
mutated in
main severely reduced these effects indicating that
ys a central role in fatty acid-controlled differentia-
dipose cells [15]. Hansen et al. [16] concluded that
activation of endogenous PPAR
in preadipocytes
e expression of PPAR but terminal differentiation
estly promoted in 3T3-L1 and NIH-3T3 cells. PPAR

in the expansion of the pool of precursor cells. The
PAR
in adipocyte differentiation could be depen-
ious types of preadipocyte cell lines, and it is true that
inly regulates adipocyte differentiation. In contrast to
dies, adipose-specific PPAR
−/− mice do not affect
ue mass [12]. Expression of activated PPAR
in adi-
(ligand independent active form of PPAR
) leads to
t features of irregular adipogenesis are not shown,
ect of PPAR
on adipocyte differentiation in 3T3-
re-confirmed [17]. Those in vivo data suggest that
ffect of PPAR
on adipose differentiation in adipose
itro is in the negative, and peripheral PPAR
func-
temic lipid metabolism more than the direct effect on
ifferentiation that might be working in PPAR
−/−