Adipocytes
13
alternative promoter usage and RNA splic-
ing. While the expression of PPAR
γ
2is
restricted almost exclusively to adipocytes,
PPAR
γ
1 has a broader pattern of expres-
sion although it is still most abundant in
adipocytes. Although PPAR
γ
2isidentica
l
to PPAR
γ
1exceptthatitcontainsanaddi-
tional 28 amino acids on its N-terminus, it
appears that the two proteins have dis-
tinct activities with regard to adipocyte
differentiation. When the expression of the
PPAR
γ
2 isoform was blocked, adipogene-
sis was more strongly inhibited than when
the PPAR
γ
1 isoform was blocked. In ad-
dition, exogenous delivery of PPAR
γ
2into
PPAR
γ
deFcient cells was able to com-
pletely restore the adipogenesis, whereas
overexpression of PPAR
γ
1 had little effect.
It may be that PPAR
γ
1, which is already
expressed in preadipocytes, behaves as a
priming factor (along with C/EBP
β
and
δ
)
for the induction of PPAR
γ
2orforthegen-
eration of endogenous PPAR
γ
ligands that
play a role in later stages of adipogenesis.
As the program of differentiation pro-
ceeds, the expression of C/EBP
α
rises
immediately after the increase in PPAR
γ
2
expression. Like PPAR
γ
,C
/
EB
P
α
also
plays an essential role in adipose devel-
opment as targeted gene knockout in mice
results in embryonic lethality and failure
to develop normal adipose tissue. There
has been an intense research effort to un-
derstand the relationship between these
two transcription factors and the role they
play in adipogenesis. Several studies have
demonstrated that PPAR
γ
2 and C/EBP
α
coregulate each other’s expression. Mice
with reduced PPAR
γ
expression due to
heterozygous gene knockout displayed a
drastically reduced level of C/EBP
α
,and
mice with disrupted C/EBP
α
expression
showed a reduced level of PPAR
γ
.In
-
troduction of either PPAR
γ
or C/EBP
α
into NIH3T3 cells is sufFcient to convert
these normally nonadipogenic cells from
Fbroblasts into adipocytes. However, it is
unc
lea
ri
fe
i
the
ro
fthet
ransc
r
ip
t
ionfac
-
tors, completely on its own, could induce
adipogenesis. Taken together, most of the
recent evidence supports the model that
while both of the transcription factors work
coordinately to carry out adipogenesis,
PPAR
γ
2 probably plays the primary role,
while C/EBP
α
may act mostly by induc-
ing and maintaining PPAR
γ
2 expression.
C/EBP
α
m
a
ya
l
s
of
u
n
c
t
i
o
nt
or
e
g
u
l
a
t
e
the transcription of genes involved in the
metabolic actions of insulin such as glu-
cose transporter 4 (Glut 4). Clearly, PPAR
γ
and C/EBP
α
are key transcription fac-
tors in adipogenesis, acting synergistically
to generate fully differentiated, insulin-
responsive adipocytes.
Although our understanding of adipo-
cyte differentiation, as described above, is
derived from work in cultured cell lines, it
is likely that many of the pathways and key
components also play an important role in
generating adipocytes from precursor cells
in vivo
and in the remodeling of adipose
tissue as it occurs during certain metabolic
stress (see Sect. 3, above) or treatment
with speciFc pharmacological agents (see
Sect. 5, below).
4
Adipose Dysfunction and Metabolic
Disease
Just as our appreciation of how active a role
the adipose tissue plays in the metabolic
regulation has grown in recent years, so too
has the interest in the role that adipocytes
play in the development (and treatment)
of metabolic diseases such as obesity and
diabetes. The investigation of the role
of adipose tissue in these diseases has
takenonaddedsigniFcanceinrecentyears
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