Adipocytes
11
that could trigger tissue expansion. As
discussed below, certain pharmacological
agents that exhibit antidiabetes properties
in rodents and man target receptors that
are enriched in fat tissue, and produce pro-
nounced tissue remodeling that is likely
related to the therapeutic actions of these
agents.
3.2
Differentiation of Adipocytes from
Precursor Cells
Together with adipocyte size, the number
of adipocytes in the body is an important
determinant of obesity and of multiple
parameters of energy metabolism. The
number of adipocytes present in an or-
ganism is determined to a large degree
by the adipocyte differentiation process
that generates mature adipocytes from
Fbroblast-like preadipocytes. Many of the
molecular details of this process are now
known, and the following section sum-
marizes our current understanding of the
molecular control of adipogenesis. It is
imp
o
r
t
an
tt
on
o
t
eth
a
tou
rund
e
r
s
t
and
-
ing of how adipocytes are generated from
precursor cells is based primarily on cell
culture models of adipogenesis such as
the mouse 3T3L1 cell line. While these
cell lines are very amenable to experimen-
tation, they produce adipocytes that are
strikingly different in some respects than
native adipocytes found in adipose tissue
in vivo
. ±or example, fully differentiated
3T3L1 adipocytes are multilocular (con-
tain multiple lipid droplets), while native
adipocytes in white fat (the predominant
type of adipose tissue in humans) display
a unilocular distribution of lipid (compare
±
igs
.2and3
)
.Wh
i
leweknowtha
tmany
of the characteristics of adipocyte differ-
entiation in cultured cell lines are also
important features of
in vivo
adipogene-
sis, it is important to bear in mind that
some aspects of adipogenesis that have
been learned from cell culture systems,
as described below, may differ from the
processasitoccurs
in vivo
.
When cultured preadipocyte cultures are
grown to confluence and cease cellular
division (growth arrest), they can be in-
duced to differentiate into adipocytes by
treatment with an adipogenic hormonal
cocktail containing insulin, dexametha-
sone, and an inducer of intracellular cAMP
concentration. One of the Frst steps in
the process of adipogenesis is the reen-
try of growth-arrested preadipocytes into
the cell cycle and the completion of sev-
eral rounds of clonal expansion. Multiple
genes involved in the cell cycle control are
required for this step to proceed, includ-
ing the tumor suppressor retinoblastoma
protein (Rb) and several cyclin-dependent
kinases and their inhibitors (p18, p21, and
p27). This and the subsequent steps of the
program of adipogenesis are controlled,
to a large degree, by a cascade of gene
expression events regulated by a small
set of transcription factors. Two families
of transcription factors have emerged as
the key determinants of this process: the
three CCAAT/enhancer-binding proteins
C/EBP
α
,
β
and
δ
, and the two-peroxisome
proliferator-activated receptors gamma-1
and gamma-2 (PPAR
γ
1 and PPAR
γ
2).
One of the initial steps in the transcrip-
tional cascade in response to adipogenic
signals is the rapid induction of C/EBP
β
and
δ
expression. These transcription
factors orchestrate cell cycle reentry by
stimulating the expression of the CDK in-
hibitor p21, which acts to inhibit the Rb
protein and relieve its block on cell cycle
progression. C/EBP
δ
and
β
have also been
shown to induce expression of the gene for
the PPAR
γ
transcription factor that plays
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