MINIREVIEW

W WAHLI, 0 BRAISSANT
AND B DESVERCNE

Peroxisome proliferator activated receptors:

transcriptional

regulators of adipogenesis,

lipid metabolism and more...

The recent discovery of lipid-activatable
transcription
factors that regulate the genes
controlling
lipid metabolism and adipogenesis has provided insight into the
way that organisms sense and respond to lipid levels. Identification
of
the signaling pathways in which these receptors are involved will
help us to understand the control of energy balance and
the molecular defects underlying
its disorders.
Chemistry &

Biology May 1995,

Free-living cells like bacteria are often exposed to dramatic

changes of their environment. They adapt to variations in
their surroundings through inducible enzyme systems that
respond to environmental signals, which often correspond
to nutritional stress. Bacteria and lower eukaryotes invoke
such systems to make use of nitrate and phosphate, metabolize sugars and synthesize amino acids and nucleotides.
In higher eukaryotes such as vertebrates, most cells of the
organism are not exposed to strong environmental fluctuations. Exceptions to this rule include the epidermis, the
digestive tract mucosa and the liver, which receives its
blood supply directly from the gut via the large portal
vein. Hepatocytes are therefore exposed to qualitative and
quantitative changes in the supply of nutrients, and sometimes to toxic compounds
taken up with food. If the
animal ingests a carbohydrate-rich
low-fat diet, the presence of glucose activates the transcription of glycolytic and
lipogenic genes in the liver. A low-carbohydrate
diet, in
contrast, induces gluconeogenic
enzymes that convert
amino acids into glucose, as well as enzymes from the
lipolytic pathway which release energy stored as triglycerides [l], while a high-fat diet stimulates genes involved
in lipid storage and expenditure [2]. Thus, there must be
factors that regulate fuel selection
according
to the
availability of glucose
and lipid, and govern their
interconversion, transport, storage, mobilization and use.
Obviously, regulation must operate on several metabolic
pathways to ensure a healthy energy homeostasis. Obesity
is one of the disorders of this balance; it is often associated
with type II diabetes, hypertension and atherosclerosis. So
far, little is known about the proteins that mediate the
nutritional signals for gene control.The
recent discovery
of the peroxisome
proliferator
activated
receptors
(PPARs), a family of lipid-activable transcription factors,
thus represents
a breakthrough
in the molecular
understanding of lipid homeostasis [3-61.
PPAR structure, distribution and activation
PPARs are members of the nuclear hormone receptor
superfamily and are relatives of the steroid, thyroid and

0 Current

2:261-266

retinoid hormone receptors [7]. All members of this superfamily share a characteristic organization of their structural
and functional domains (see Fig. la). PPARs are activated
by a diverse group of substances called the peroxisome
proliferators, which induce massive proliferation of peroxisomes in rodent hepatocytes. The group includes fibrate
hypolipidemic drugs such as clofibrate (see Fig. lb) as well
as certain plasticizers and herbicides. The nature of the
molecular mechanism by which these various amphipathic
carboxylates activate PPARs is still unclear.
PPARs form a distinct subfamily within the superfamily
of nuclear hormone receptors, with at least three gene
loci in all the species thus far studied.These
are OL,B and
y in Xenopus laevis [4], (Y, 6 and y in mouse [8] and o,
NUC-1
and y in man [7,9,10]. Evolutionary
analyses
show that the (Y and y loci in different species are
homologous,
but it is not clear whether the Xenopus B
gene is the homolog of the mouse 6 and human NUC-1
genes [7]. In Xeno~~, PPARor and B are expressed in
oocytes and early embryos, whereas in rodents it is
PPARS that is present at early stages [4,8]. In adults of all
species tested, the PPARol gene is highly expressed in
tissues with high lipid metabolism
(liver, kidney, white
and brown adipose tissues) and is transcriptionally
regulated by glucocorticoids
in liver [3,4,8,11].
PPARB
(Xenopus) or 6 (rodents) app ears to be expressed ubiquitously, albeit at a low level in liver. PPARy is observed at
a high level in white adipose tissue and spleen of rodents
[8,12] and in fat bodies of Xenopus [4].
Although PPARs were named by virtue of their activation by peroxisome proliferators, the finding that natural
fatty acids (such as linoleic acid; see Fig. lb) activate
them as well raises the question of whether fatty acids are
the true ligands. If so, this would suggest that nutrient
derivatives can act on gene regulation in the same way as
steroid or thyroid hormones.
So far, it appears that no
one fatty acid exclusively activates a given PPAR subtype
[5,6,13]. Fatty acids with a chain length of 10 or more
carbons activate PPARs from several species, while those

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Chemistry & Biology 1995, Vol 2 No 5

(a)
DNA binding domain
Ligand binding domain
Transactivation domains v-__~-

CYTOPLASM
NUCLEUS

pz%Esym:]
Peroxisome

Proliferator

Response Element

-)

Fig.1. Peroxisome proliferator activated

receptors (PPARs) and PPAR activators.
(a) PPARs are organized into six structural and functional
domains (A-F), like
the steroid
hormone
receptors.
The
main functions of domains A/B, C and E
are indicated. The DNA-binding
domain
C is characterized by two zinc fingers of
the C4 subtype. The P box in the first
finger is responsible for specific recognition of the response element.and
the
D box in the second finger, characteristically
containing
only three aminoacids
in
PPARs,
is
involved
in
dimerization.
PPARs regulate transcription of their target genes by heterodimerization
with the 9-cis retinoic acid
receptor,
also called the retinoid
X
receptor (RXR). In the promoter region
of target genes, the PPAR/RXR heterodimer binds to a specific peroxisome
proliferator
response element, which is
a direct repeat of the AGGTCA motif
with one nucleotide
spacing. (b) PPAR
activators. PPARs are activated by long
chain fatty acids (natural fatty acids
such as linoleic acid), peroxisome
proliferators
(including
hypolipidemic
drugs such as clofibrate),
and thiazolidinediones
such as BRL 49653
(an
antidiabetic agent).

(b)
Linoleic Acid (Cl 8:2w6)
GYCOOH
CH3

Clofibrate
CH3

BRL49653

with shorter chains are much less active.With the exception of Xenopus PPARor, which has a preference
for
polyunsaturated fatty acids rather than mono-unsaturated
or saturated fatty acids, the position (o-3 versus o-6) or
number of unsaturated bonds appear to have no major
effects. Interestingly, o-3 fatty acids, like hypolipidemic
drugs, lower serum lipid concentrations,
suggesting that
they may preferentially activate a PPAR subtype that is
involved in controlling lipid uptake or breakdown.
Although it is not yet clear to what extent PPAR subtypes can be specifically activated by different fatty acids,
they are distinct with respect to their activation by
various synthetic or natural compounds. Pirinixic acid
(Wy14,643),
an experimental
hypolipidemic
drug, is a
potent activator of mouse PPARcx but not of PPARG and
y [8]. Similarly, the arachidonic acid analog ETYA, so far
the most potent activator of Xenopus PPARcY, does not
activate PPARB
and y [13]. Significant
activation of

mouse PPARy is obtained with the leukotriene

antagonist LY-171883 and, more interestingly, with an antidiabetic thiazolidinedione
(BRL49653;
see Fig. lb), which
binds to this subtype with a K, of 40 nM [14]. For mouse
PPARG, the most potent activator known is linoleic acid
[S]. The PPAR subtyp es may therefore respond differentially to various physiological activators as well. Together
with the varying expression of the receptor subtypes, such
differential regulation would allow this receptor family to
fulfill a number of distinct functions during development
and in adulthood.
Dimerization
is essential for the function of most of the
members of the hormone receptor superfamily. This holds
also for the PPARs; they heterodimerize
with the 9-cir
retinoic acid receptor (R2CEQ, forming a complex that can
stimulate gene activity. The dimer of PPAR and RXR
binds to a hormone-response
element located in the promoter region of target genes. This element comprises a

lipid-activated

direct

repeat

of

the

AGGTCA

motif

with

a one-

nucleotide spacer between the two half-sites (Fig. la)

[5,15]. The physiological
consequences
of this convergence between the signaling pathways of fatty acids and
retinoids through PPAR/RXR
heterodimers remain to
be elucidated. It is clear from the involvement of RXR in
the action of PPAR that there must be some crosstalk
with the receptors for thyroid hormone, all-tvuns retinoic
acid and vitamin D, which all also have RXR as a partner.
There is, of course, ample evidence that retinoids, thyroid
hormones and vitamin D are important in development
and cell differentiation. So far, however, there is little evidence for a function of PPARs in cellular differentiation,
with the exception of their involvement in adipogenesis
[16,17] and possibly in the formation of the lipid barrier
in the epidermis [18].
Table 1. Genes regulated by fatty acids (FA) and peroxisome

transcription

Wahli et a/

Role of PPAR in adipogenesis

Adipocytes

are of central importance

in lipid storage and

in the regulation of energy balance.They

store energy in
the form of triglycerides when food availability is high
and release it in the form of free fatty acids under conditions of energy expenditure
[19]. The expansion
of
adipose tissue mass when excess food is ingested requires
differentiation
of adipocytes from precursor cells. If the
signal to differentiate is an elevated level of plasma lipids,
a direct signal transduction pathway similar to that used
by lipophilic hormones (steroids, thyroid hormones) can
be envisaged, in which a lipid-activated
transcription
factor senses the hyperlipidemic state and triggers adipogenesis. Such a pathway would be similar to the one that
controls the release of the sterol regulatory
element
binding proteins [20]. These transcription
factors are

proliferators

(PP).
FAIPP

PPARs

References

-/+a
+
+
n.d.
n.d.
n.d.

WI
[261
[271
1281,b
[291
[301
[311
[311

Hepatocytes
1. Extra- and intra-cellular

FA transport

1 .I: L-FABP (liver fatty-acid-binding protein)

1.2: Apolipoprotein Al
1.2:Apolopoprotein A II
1.2: Lipoprotein lipase
1.2: Apolipoprotein C-III
1.3: Carnitine-palmitoyl
transferase 1
1.4: Carnitine-acyl transferase
1.5: Carnitine-octanoyl
transferase
2. Mitochondrial
Medium

+
+
+
+
+
+

n.d.

P-oxidation

chain acyl-CoA dehydrogenase

-I-

t321

+
+
+
+

+
+
+
n.d.

[331
I41
[341
t311

[351

[361

[3 71

+
+

+
n.d.

t221

[381

3. Peroxisomal P-oxidation
Acyl-CoA synthetase
Acyl-CoA oxidase
Enoyl-CoA hydratase/3-OH-acyl-CoA
3-Ketoacyl-CoA thiolase

dehydrogenase

4. Microsomal w-oxidation
P450 4A6 (fatty acid w-hydroxylase)
5. Ketone body synthesis
HMG-CoA

synthase

6. Fatty acid synthesis

Malic enzyme

Adipocytes
1. Extra- and intra-cellular

FA transport

1 .I : aP2 (adipocyte lipid-binding protein)

1 .I : MAL-1 (keratinocyte-lipid
binding protein)

1121

7. Glyceroneogenesis
Phosphoenolpyruvate

carboxykinase

(PEPCK)

Some of the genes (bold) are direct targets of PPARs. FA/PP-regulated genes have been studied mainly in hepatocytes (top) and
adipocytes (bottom), where they are involved in various lipid metabolic pathways (numbered 1 to 7). Stimulation (+) or repression
(-) of gene activity either by FNPP or by PPARs is indicated. n.d.: direct regulation by PPARs not yet determined.
aFibrates down-regulate
the transcription
of the APO-AI gene independently
of PPARs, whereas PPARs can overcome
this
down-regulation
via a functional
PPRE in the APO-AI promoter.
bK. Schoonjans, B. Staels, S. Deeb and 1. Auwerx, personal communication.

263

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Chemistry & Biology 1995, Vol 2 No 5

Fig. 2. Main lipid metabolic pathways

regulated by PPAR target genes. PPARs
are involved
in (1) the regulation
of
fatty acid extra- and intra-cellular
transport, (2) mitochondrial
p-oxidation,
(3)
peroxisomal
P-oxidation,
(4) microsomal w-oxidation,
(5) mitochondrial
ketone body synthesis,
(6) fatty acid
synthesis
and (7) glyceroneogenesis.
The pathways are numbered as in Table
1. TC, triglycerides;
FFA, free fatty
acids; PL, phospholipids;
FABPs, fatty
acid binding proteins.

TC \

FFA

pyruvate

glyceroneogenesis
+

glycerol

FABPs

-FFA

Triglycerides

I
@ FA synthesis
;

sensors of sterol levels and are synthesized as membranebound precursors. They are proteolytically
cleaved and
released as active nuclear factors only in the absence of
sterols.When
sterols overaccumulate in cells as a result of
high cholesterol diets, precursor cleavage is abolished and
the expression of target genes, such as the gene for the
low density lipoprotein receptor, declines.
The first transcription
factor identified as a potential
of the
adipose
differentiation
process,
regulator
C/EBPa,
did not meet the requirements
for a lipid
overload sensor because it does not appear to bind or to
be activated by fatty acids [21]. Nevertheless,
this basic
leucine zipper transcription
factor binds to the promoters of several genes expressed in adipocytes, and can
induce the adipogenic program in a variety of fibroblastic cells. It is thus thought to be involved in adipogenesis control possibly through a combined
action with
PPAR [17]. Indeed, PPARy seems likely to be involved
in the regulation of adipose cell number in response to
variations in lipid flux. It is highly expressed in fat
tissues and it has been recently shown to activate the
program of adipocyte gene expression and to stimulate

adipose
differentiation
of cultured
fibroblasts
in a
PPAR-activator-dependent
manner [16,17]. Increased
levels of fatty acids or fatty acid metabolites
may activate PPARy, in turn stimulating adipogenesis. WEBPa
cooperates with PPARy to stimulate this differentiation
program, suggesting that both transcription
factors are
required for the development
of adipose cells from
uncommitted
mesodermal precursors [17].These
observations suggest that it may be possible to develop synthetic compounds
that would bind to PPARy
and
interfere with the regulation of the number of adipose
cells in the organism.
Regulation of lipid metabolism
PPAR subtypes are also expressed in a variety of nonadipose tissues, where they are probably also engaged in
lipid metabolism.
So far, however, the identification
of
PPAR target genes has concentrated
mainly on hepatocytes and adipocytes, because of their importance in systemic lipid metabolism. The target genes identified so
far are summarized in Table 1. These control key functions of lipid metabolism, such as transport and cellular
uptake of lipids, intracellular balance between free and

Lipid-activated

bound fatty acids, conversion of fatty acids to their activated CoA form, penetration
of fatty acids into membrane-delimited
organelles,
microsomal
w-oxidation,
mitochondrial
P-oxidation
peroxisomal
P-oxidation,
and ketogenesis, as well as the production of glycerol for
triglyceride synthesis. Indeed, essentially all of the major
pathways of lipid metabolism
appear to be under the
control of one or more PPAR-regulated
genes. These
pathways are often regulated at several levels, allowing
fine-tuning of the whole network response to a stimulus
(Fig. 2). Thus, lipids control their own metabolism,
mainly
by controlling
transcription
of the genes

The homeostasis

cellular and physiologic pathways (see Fig. 2), changes our

view of lipids from mainly passive to active participants in
cell differentiation and metabolic regulation.
PPAR in health and disease: future prospects
Disorders
like obesity, hyperlipidemia,
atherosclerosis
and type II diabetes are often causally linked to each
other and associated with the dysfunction
of genes
implicated
in energy homeostasis
in a broad sense.
Although not all of these will be genes that are directly
regulated by PPARs, the interdependence
of the systems
that regulate the supply of energy and those that regulate lipid metabolism
suggests that manipulation
of
PPAR target genes might have therapeutic benefits. For
example, fibrate hypolipidemic
drugs and thiazolidinediones, a new class of antidiabetic agents that improve
insulin sensitivity
in rodent models of non-insulindependent diabetes mellitus (NIDDM),
appear to act via
PPARs [3,4,14,22].
However, the link between the activation of PPARy by antidiabetics
of this class and the
reduction
of plasma glucose, triglyceride
and insulin
levels that these compounds induce remains unclear (see
[14]). The action of PPARy
may regulate endocrine
functions of the adipose tissue, for instance by modulating the production and release of the product of the ob
gene, which is mutant in obese mice [23], and ofTNFol,
which affects insulin signaling [24]. The discovery of
new PPAR-subtype-specific
agonists
or antagonists
should prove very valuable for a better understanding of
the signaling cascade of each subtype, and will help us
understand how lipid and energy levels are controlled
during normal development
and in adulthood. There is
no doubt that further investigations
on PPARs will
provide answers to some of the long-standing
questions
regarding the contribution
of adipogenesis
and lipid

et a/

defects

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functions. In this
article, we have addressed only one aspect of this complex
network, namely the control by lipids of their own
metabolism. The discovery that fatty acids can activate
transcription
factors, and can therefore regulate many

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Switzerland and Institute ofAnimal Biology, University of
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