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Departments of Biochemistry and Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI 53706
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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KEY WORDS: • adipose tissue • differentiation • preadipocytes • transcription factors
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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) and hypertension
(Spiegelman et al. 1993
). Obesity has also been linked
to some types of cancers, immune dysfunction and, in a
self-perpetuating manner, obesity (Spiegelman et al. 1993
). The molecular link to cancer has not been strongly
established but is believed to be related to an increase in free
radical damage of DNA caused by an increase in fatty acid metabolism. A
thorough understanding of the differentiation process would allow for
manipulation of adipocyte cell number and control of certain diseases.
The study of the molecular mechanisms of adipocyte development may
suggest important patterns for comparison to other developmental
systems and may provide an understanding of the physiology, in general,
of late animal development. This article will discuss the various
models used for studying the preadipocyte differentiation process, with
the 3T3-L1 cell culture line described in detail. We focus on those
genetic events that link exogenous effectors to induction of adipocyte
gene expression in sequence. More detailed insight in transcriptional
activation and repression of adipocyte genes and other aspects of
adipocyte biology have been discussed in several excellent reviews
(Cornelius et al. 1994
, Cowherd et al. 1999
, Gregoire et al. 1998
, Lane et al. 1999
, MacDougald and Lane 1995
Mandrup and Lane 1997
, Miller and Ntambi 1998
,
Morrison and Farmer 1999
, Vasseur-Cognet and Lane 1993
). |
Models of preadipocyte differentiation |
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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. A single fertilized egg gives rise to nearly 200 different cell types
that make up the multiple developmental lineages and multicellular
organism. The full developmental program of preadipose tissue from
fertilized egg is unknown. However, the pluripotent fibroblasts (stem
cells) are known to have mesodermal origins (Cornelius et al. 1994
) and can differentiate into committed preadipocytes,
cartilage, bone or muscle tissue. In humans, preadipocytes begin to
differentiate into adipose tissue during late embryonic development,
with a majority of the differentiation occurring shortly after birth
(Burdi et al. 1985
). This enables the newborn to cope
more efficiently with intervals between nutrient intake
(MacDougald and Lane 1995
). Rat and mouse preadipocytes
do not begin conversion into adipose tissue until after birth
(Ailhaud et al. 1992
). All species have the ability to
differentiate preadipocytes throughout their life spans in response to
the body’s fat storage demands.
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). The distinction
between preadipocytes and fibroblasts is difficult to make, and the
inability to align preadipocytes at similar developmental stages
confounds detailed in vivo studies. To some extent, preadipocyte
primary culture has been used. However, the use of primary culture
suffers major drawbacks. First, it is difficult to isolate
preadipocytes from other fibroblast-like cells. Second, large
amounts of fat tissue are required because preadipocytes constitute
only a small percentage of total fat tissue. In addition, primary
cultures have a limited life span in culture. Preadipocyte differentiation has therefore been studied primarily by using in vitro models of adipogenesis; much of the knowledge of adipocyte differentiation has been based on the validity of these tissue culture models. There are advantages and disadvantages to using a cell line to study preadipocyte differentiation. A cell line derived from cloning is homogenous in population of cells that are all at the same stage of differentiation. This allows for a definitive response to treatments. In addition, these cells can be passaged indefinitely, which provides a consistent source of preadipocytes for study.
Adipocyte precursor cell lines can be segregated into two
classes, i.e., pluripotent fibroblasts and unipotent preadipocytes. The
pluripotent fibroblasts (10T1/2, Balb/c 3T3, 1246, RCJ3.1 and CHEF/18
fibroblasts) have the ability to be converted into several cell types.
10T1/2 fibroblasts, which were derived from C3H mouse embryos
(Reznikoff et al. 1973
), can be converted to preadipose,
premuscle and precartilage tissue upon treatment with 5-azacytidine, an
inhibitor of DNA methylation (Taylor and Jones 1979
).
These multipotent fibroblasts act as good models for understanding the
events responsible for cellular determination of the separate cell
fates. Such work led to the discovery of MyoD as a critical regulator
of muscle cell determination (Edmondson and Olson 1993
).
The second class of culture cells, the unipotent preadipocytes
(3T3-L1, 3T3-F422A, 1246, Ob1771, TA1 and 30A5), have undergone
determination and can either remain as preadipocytes or undergo
conversion to adipose tissue. They are ideal for studying the molecular
events responsible for the conversion of preadipocytes into adipocytes.
The 3T3-L1 and 3T3-F422A culture lines, derived from disaggregated
Swiss 3T3 mouse embryos (Green and Kehinde 1974
), are
the most widely used culture models. TA1 (Chapman et al. 1984
) and 30A5 preadipocytes (Konieczny and Emerson 1984
), obtained from 5-azacytidine treatment of 10T1/2
fibroblasts, have also been used. Ob1771 preadipocytes, obtained from
genetically obese adult mice, are used to investigate aspects of
differentiation resulting from genetic obesity (Negrel et al. 1978
). The 1256 cell line has been used to study the effects of
fatty acids on adipocyte differentiation (Serrero et al. 1992
). There is some variation in the differentiation
requirements of each cell line. It is believed that these differences
represent variations in the developmental stage at which cells were
arrested when derived (Cornelius et al. 1994
,
Smas and Sul 1995
). The identification of specific
developmental markers will allow (and has to some extent) for the
alignment of the developmental programs of the various cell lines.
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Progression of differentiation in 3T3-L1 preadipocytes |
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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). In culture, differentiated
3T3-L1 preadipocytes possess most of the ultrastructural
characteristics of adipocytes from animal tissue (Novikoff et al. 1980
). The formation and appearance of developing fat
droplets also mimic live adipose tissue (Green and Kehinde 1974
).
Confluent 3T3-L1 preadipocytes can be differentiated
synchronously by a defined adipogenic cocktail. Maximal differentiation
is achieved upon treatment with the combination of insulin, a
glucocorticoid, an agent that elevates intracellular cAMP levels, and
fetal bovine serum (Student et al. 1980
).
Insulin is known to act through the insulin-like growth factor 1
(IGF-1) receptor. IGF-1 can be substituted for insulin in the
adipogenic cocktail (Smith et al. 1988
). Dexamethasone
(DEX), a synthetic glucocorticoid agonist, is traditionally used to
stimulate the glucocorticoid receptor pathway. Methylisobutylxanthine
(MIX), a cAMP-phosphodiesterase inhibitor, is traditionally used to
stimulate the cAMP-dependent protein kinase pathway. This
adipogenic cocktail, containing MIX, DEX and insulin, is commonly
abbreviated MDI.
Approximately 24 h after induction by MDI, differentiating
preadipocytes undergo a postconfluent mitosis and subsequent growth
arrest (Bernlohr et al. 1985
). The cells undergo at
least one round of DNA replication and cell division. By d 2 of
differentiation, the cells complete the postconfluent mitosis and enter
into an unusual growth arrest called GD
(Scott et al. 1982
). The mitosis is believed necessary
to unwind DNA, allowing transcription factors access to regulatory
response elements present in genes involved in modulating the mature
adipocyte phenotype (Cornelius et al. 1994
). After the
growth arrest, cells are committed to becoming adipocytes. The growth
arrest is required for subsequent differentiation. Growth-arrested
cells begin to express late markers of differentiation at d 3. These
late markers consist of lipogenic and lipolytic enzymes, as well as
other proteins responsible for modulating the mature adipocyte
phenotype. The cells then round up, accumulate fat droplets and become
terminally differentiated adipocytes by d 5–7.
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Gene expression during 3T3-L1 preadipocyte differentiation |
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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constitute a direct pathway linking exogenous effectors to adipocyte
gene expression through a sequence of transcriptional steps that are
aligned in series. At confluence, 3T3-L1 preadipocytes express very
early markers of adipocyte differentiation. The cell-cell contact
induces the expression of lipoprotein lipase and type VI collagen genes
(Cornelius et al. 1988
, Dani et al. 1990
). Within 1 h after the addition of MDI, the
expression of c-fos, c-jun, junB,
c-myc and CCAAT/enhancer binding proteins (C/EBP) ß and
is observed (Cornelius et al. 1994
). Fos and jun
proteins have not been implicated directly in any
differentiation-specific events. On the basis of their roles in
other systems, they are believed to have mitogenic properties.
c-myc has been shown to initiate mitogenesis in
differentiating preadipocytes (Cornelius et al. 1994
).
Enforced expression of the c-myc oncogene was shown to block
cell differentiation, which was reversible upon high expression of
c-myc antisense RNA (Freytag 1988
). This suggests
that c-myc expression may be a branch point at which the growth
arrested cells are either directed toward cell cycle reentry or
committed to terminal differentiation. The expression of
c-fos, c-myc and c-jun is transient,
dissipating by 2–6 h after treatment with MDI.
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are the first transcription factors induced
after exposure of the preadipocytes to the differentiation cocktail;
they are therefore postulated to be involved in directing the
differentiation process. In accord with this notion, expression of
C/EBPß or C/EBP under the control of exogenous promoters of
differentiation induces and accelerates adipogenesis in response to
hormonal inducers. C/EBPß is responsive primarily to DEX, whereas
C/EBP is responsive primarily to MIX. After removal of MIX and DEX
from the culture medium, expression of C/EBP dissipates over the
subsequent 48 h, whereas the decline of C/EBPß is more gradual
such that by d 8, its expression is 
0% of maximal levels
(Erickson et al. 2000
, Lane et al. 1999
).
The activity of C/EBPß and is thought to mediate the expression
of peroxisome proliferator-activated receptor 
(PPAR)
(Clarke et al. 1997
, Wu et al. 1995
),
which is transcriptionally induced during the 2 d after induction
of differentiation and is maximum by d 3–4. It also appears that
C/EBPß and mediate the expression of C/EBP
, which increases
from undetectable levels in preadipocytes to detectable levels 2 d
after MDI stimulation and to full expression 5 d after initiation of
the differentiation program (Christy et al. 1991
,
Lin and Lane 1994
). Once activated, PPAR and
C/EBP cross-regulate each other to maintain their gene
expression despite a reduction in the expression of C/EBPß and
(Shao and Lazar 1997
). PPAR and C/EBP alone or in
cooperation with each other induce the transcription of many adipocyte
genes encoding proteins and enzymes involved in creating and
maintaining the adipocyte phenotype (Gregoire et al. 1998
).
C/EBP and PPAR are being studied in great detail with the
hope of identifying an adipocyte-specific master switch for
terminal differentiation. Although both factors are critical for the
late stages of differentiation in a cooperative and synergistic manner,
neither factor is expressed at high levels in preadipocytes and
therefore cannot be involved in early development. Furthermore, unlike
coexpression of these two factors, ectopic expression of either
transcription factor does not promote differentiation to the same
extent as the full differentiation initiated by the hormonal MDI
cocktail (Brun et al. 1996
, Hu et al. 1995
, Tontonoz et al. 1994
).
The antimitotic activity of C/EBP prevents postconfluent
mitosis when added to preadipocytes (Umek et al. 1991
).
This prevents the cells from progressing through intermediate
differentiation. Forced expression of PPAR in preadipocytes does not
cause differentiation without the addition of an exogenous ligand
(Tontonoz et al. 1994
). This indicates that an
endogenous PPAR ligand is not present in 3T3-L1 preadipocytes. The
endogenous ligand must be produced in response to MDI during the course
of early differentiation. The upregulation of ADD1/SREBP-1c gene
expression that occurs during preadipocyte differentiation
(Ericsson et al. 1997
) is thought to lead to the
production of endogenous PPAR ligands required for transcriptional
activity (Kim et al. 1999
). These endogenous ligands
believed to be fatty acid–like molecules, have not been identified and
are now the focus of several investigations.
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Summary |
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by a grant from the American Heart
Association.
4 Abbreviations used: C/EBP, CCAAT/enhancer
binding protein; DEX, dexamethasone; IGF-1, insulin-like growth
factor 1; MDI, adipogenic cocktail containing MIX, DEX and insulin;
MIX, methylisobutylxanthine; NIDDM, noninsulin-dependent diabetes
mellitus; PPAR, peroxisome proliferator-activated receptor.
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TOPABSTRACTINTRODUCTIONModels of preadipocyte...Progression of differentiation...Gene expression during 3T3-L1...SummaryREFERENCES |
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