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Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT Pleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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(PPAR) and
CCAAT/enhancer binding protein-
(C/EBP). These prominent
adipogenic transcription factors have been shown to regulate, directly
or indirectly, the gene expression necessary for the development of the
mature adipocyte. Hormonal and nutritional signaling that impinges on
these trans-acting factors provides a molecular link
between lipids and lipid-related compounds and the gene expression
important for glucose and lipid homeostasis. Knowledge concerning the
transcriptional events mediating adipocyte differentiation provides a
basis for understanding the physiologic processes associated with
adipose tissue as well as for the development of therapeutic
interventions in obesity and its related disorders.
KEY WORDS: • energy metabolism • adipose tissue • transcription • gene expression • peroxisome proliferator–activated receptor-
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Pleiotropic functions of the adipocyte |
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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]. These findings gave new incentive to adipose tissue
research that has resulted in new discoveries and reconsideration of
previously ascribed functions, positioning the adipocyte near the
center of physiologic processes mediating energy metabolism as well as
a plethora of potentially unrelated functions.
As illustrated in Figure 1
, adipocyte functions can be grouped generally into three categories
with potentially overlapping modalities. Processes associated with
lipid metabolism are best exemplified by the storage and release of
fatty acids for vitally important processes such as myocardial
contraction during times of need. Secretion of glycerol and fatty acids
from the adipocyte also plays an important role in hepatic and
peripheral glucose metabolism. Moreover, adipose tissue as well as
heart and skeletal muscle are the only known tissues to express and
regulate the insulin-dependent glucose transporter, Glut4, which
facilitates the entry of glucose into these cells and out of
circulation postprandially. Emerging data suggest that the adipocyte
also plays an important role in numerous processes through its
secretory products and endocrine functions. In this regard, leptin has
a wide spectrum of biological activities, independent of satiety,
including effects on fertility, reproduction and hematopoiesis. In
addition to this hormone, adipose tissue secretes a variety of
peptides, cytokines and complement factors whose various functions are
linked inseparably to the adipocyte as a source for their production
[reviewed in Gregoire et al. (1998)
].
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). Genetic mutations that alter the release of leptin from the adipocyte
or suppress its interaction with receptors in the hypothalamus are
well-known causes of obesity in mice. Cytokines and lipids released
from adipose tissue may lead to a decrease in glucose utilization in
skeletal muscle and enhance glucose production by the liver, both of
which contribute to high levels of glucose in the peripheral
circulation, a hallmark of noninsulin-dependent diabetes mellitus.
Furthermore, cytokines from the adipocyte may play a role in activating
various inflammatory responses that are considered to be important
mediators of cardiovascular disease. In addition, the development of
atherosclerotic lesions is likely to be compounded by hyperlipidemia
contributed to by the release of fatty acids from fat-laden
adipocytes.
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). Knowledge concerning
the sequence of transcriptional events during adipogenesis provides a
basis for understanding the physiologic processes associated with
adipose tissue as well as for the development of therapeutic
intervention in adipocyte-related disease. |
Transcription factors regulating adipocyte differentiation |
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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300 proteins. The directional
change of many of these proteins has been reviewed comprehensively
(Cornelius et al. 1994
). Many of these changes occur at
the level of gene expression through a series of molecular events
involving several transcription factor families that exhibit diverse
modes of activation and function. The following represent only the more
prominent trans-acting factors that are currently considered
to play a regulatory role in the process of adipogenesis. Peroxisome proliferator–activated receptors.
The peroxisome proliferator–activated receptors
(PPAR)4are a subset of the nuclear hormone receptors whose transcriptional
activities are modulated by ligand-receptor interactions [reviewed
in Brun and Spiegelman (1997)
]. The three known PPAR
family members, PPAR, PPAR and PPAR
, bind similar peroxisome
proliferator response elements, but exhibit different transactivating
functions, which are mediated in part by tissue distribution, ligand
specificity and coactivator recruitment. Through utilization of
different start sites and alternate splicing, the PPAR gene gives
rise to two isoforms, 1 and 2. PPAR2 is highly enriched in
adipose tissue and generally mediates gene expression regarding fatty
acid metabolism. The notion that PPAR plays a major role in
regulating adipogenesis is supported by the fact that
thiazolidinediones (TZD), which are high affinity, synthetic ligands
for PPAR, are potent inducers of adipocyte differentiation.
Furthermore, ectopic expression of PPAR in multiple nonprogenitor
cells lines under adipogenic conditions results in consistent and
potent induction of adipocyte differentiation. Gene ablation studies
reporting an absence of white adipose tissue have positioned PPAR
and its obligate heterodimeric partner, retinoid X receptor
(RXR), as prominent transcription factors in regulating the gene
expression leading to adipogenesis (Barak et al. 1999
,
Kubota et al. 1999
, Rosen et al. 1999
).
CCAAT/enhancer-binding proteins.
The CCAAT/enhancer-binding proteins (C/EBP) belong to a large family of
leucine zipper transcription factors, which function through homo- and
heterodimeric complexes with C/EBP family members. Three of these
family members, C/EBP, C/EBPß and C/EBP, are expressed in both
white and brown adipose tissue and have been studied and reviewed
extensively for their roles in regulating adipogenesis
(Darlington et al. 1998
, Lane et al. 1996
). Ectopic expression of C/EBP or C/EBPß induces
adipogenesis in nonprogenitor fibroblasts, whereas antisense expression
of C/EBP inhibits differentiation of cultured preadipocytes. Gene
ablation studies that target C/EBP or combined C/EBPß and C/EBP
demonstrate a reduced propensity for adipogenesis, with deficient
animals developing markedly less adipose tissue compared with
wild-type littermates. Collectively, these data demonstrate an
important role for C/EBP family members during the development of
adipocyte differentiation, in vitro and in vivo.
ADD1/SREBP-1c.
Sterol regulatory element binding proteins (SREBP) are known to
modulate transcription of numerous genes encoding proteins that
function in both cholesterol and fatty acid metabolism [reviewed in
Brown and Goldstein (1997)
]. The SREBP family consists of three
proteins, designated SREBP-1a, -1c and -2, which are encoded by two
independent genes. In humans and mice, SREBP-1a and SREBP-1c are
produced from a single gene through the use of alternate transcription
start sites. Adipocyte determination- and differentiation-dependent
factor 1 (ADD1), cloned independently from a rat adipocyte cDNA library
(Tontonoz et al. 1993
), is homologous to human SREBP-1c.
Although all three SREBP are capable of activating similar gene
expression, regulation of fatty acid biosynthesis is mediated primarily
by SREBP-1a and ADD1/SREBP-1c. In vivo, adipose tissue expresses
predominantly ADD1/SREBP-1c over other forms of SREBP, and ectopic
expression of a constitutively active form of ADD1/SREBP-1c enhances
adipocyte gene expression in nonprogenitor NIH-3T3 fibroblasts under
adipogenic conditions. In addition, expression of a dominant negative
form of this SREBP isoform represses 3T3-L1 preadipocyte
differentiation (Kim and Spiegelman 1996
). Although
ablation of the SREBP-1 gene (mice lacking both SREBP-1a and SREBP-1c)
has been reported to have little effect on white adipose tissue mass,
redundancy of function (i.e., SREBP-2 expression) has not been ruled
out (Shimano et al. 1997
) .
STATs.
Signal transducers and activators of transcription (STATs) comprise a
family of cytoplasmic proteins that are activated by and mediate gene
expression in response to extracellular effectors that target receptors
with intrinsic kinase activity or receptors to which Janus
kinases (JAK) are bound [reviewed in Darnell (1997)
].
Ligand-mediated dimerization of the receptor results in
phosphorylation of the associated kinase, which subsequently
phosphorylates the cytoplasmic tail of the receptor that serves as a
docking site for STAT recruitment. The receptor-bound STAT is
phosphorylated, then dimerizes with other STAT proteins and
translocates to the nucleus to mediate specific gene expression.
The expression of three members of this family, STAT1, STAT5A and
STAT5B, is upregulated during differentiation of cultured preadipocytes
(Stephens et al. 1996
). Although the function of STATs
during adipocyte differentiation is unclear, gene ablation of STAT5A
and STAT5B produces animals with markedly less white adipose tissue
compared with wild-type littermates, demonstrating a significant
role for these proteins during adipogenesis (Teglund et al. 1998
).
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Cascade of transcriptional events mediating adipogenesis |
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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. The 3T3-L1 preadipocyte cell line can be "induced to
differentiate" with the addition of mitogens and hormonal agents
(e.g., insulin, glucocorticoids and agents that lead to an increase in
cAMP); this initiates a cascade of transcriptional events that
collectively account for the expression of most proteins mediating
adipocyte function. Immediately after exposure to exogenous mediators,
the gene expression of C/EBPß and C/EBP significantly and
transiently increases (Fig. 2)
, marking an event that is likely to
distinguish a preadipocyte from a nonadipogenic precursor cell
(Cao et al. 1991
). The activity of these C/EBPs then
mediates the expression of PPAR (Clarke et al. 1997
,
Wu et al. 1995
), which forms a functional heterodimer
with RXR. Although yet unproven, a consensus sequence in the
C/EBP promoter suggests that C/EBPß and C/EBP may also regulate
the expression of C/EBP (Christy et al. 1991
,
Lin et al. 1993
). Once activated, PPAR and C/EBP
appear to cross-regulate each other, thus maintaining their gene
expression despite the ensuing decay of C/EBPß and C/EBP
(Schwarz et al. 1997
, Shao and Lazar 1997
). Although data suggest that C/EBP may also have the
capacity to autoregulate its own expression, recent studies have
demonstrated that ectopic expression of PPAR is not capable of
activating endogenous PPAR gene expression in C/EBP-deficient
fibroblasts (Wu et al. 1999
).
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and C/EBP gene expression. For example, exposure of
preadipocytes to mitogens and hormonal agents that induce
differentiation also leads to an early upregulation of ADD1/SREBP-1c
gene expression (Ericsson et al. 1997
). It has been
postulated that this SREBP family member also plays a role in
upregulating PPAR gene expression (Fajas et al. 1999
). Moreover, evidence suggests that ADD1/SREBP-1c may be
involved in gene expression that leads to the production of endogenous
PPAR ligands required for transcriptional activity (Kim et al. 1999
). Other studies have demonstrated that
undifferentiated preadipocytes express a number of inhibitory proteins
that must be repressed or functionally inactivated to allow the
differentiation process to occur. Exposure of preadipocytes to
differentiating agents leads to repression of AP-2 and SP1
transcriptional activity, events that are necessary for PPAR and
C/EBP gene expression (Jiang et al. 1998b
,
Tang et al. 1999
). Inhibitory molecules may function, in
vivo, to maintain the preadipocyte phenotype until hormonal and
nutritional conditions are supportive for adipocyte differentiation.
Similar paradigms are now considered dogma in cell proliferation
pathways in which numerous proteins serve check-point functions
regulating commitment to cell cycle progression.
After their expression, PPAR and C/EBP are considered to play a
prominent role in regulating the gene expression of proteins necessary
for the development of the functional mature adipocyte. To date,
however, only a limited number of the exhaustive list of genes encoding
for proteins mediating adipocyte function are known to contain active
consensus sequences for either PPAR or C/EBP. It is conceivable
that these potent adipogenic transcription factors can modulate
indirectly the expression of other genes through the activation of
intermediary trans-acting factors. In this regard, recent
evidence indicates that the differentiation-dependent induction of
STAT1, STAT5A and STAT5B is regulated downstream of PPAR in the
differentiation paradigm (Fig. 2)
(Stephens et al. 1999
). Although complete adipocyte differentiation requires the
expression of STAT5, the precise function that indirectly links the
activity of PPAR to adipocyte gene expression has yet to be
determined. Although future studies will undoubtedly identify other
unknown transcription factors downstream of PPAR and/or C/EBP,
activation of STAT expression represents the only known regulation of
trans-acting factors by either of these adipogenic
mediators.
Any property of the mature adipocyte is likely to require the
expression of numerous genes that collectively account for that
specific function. With this in mind, PPAR and C/EBP have been
shown to transactivate subsets of genes as a function of either
trans-acting factor alone or one requiring the cooperative
efforts of both. An example of this is also noted when expressing
PPAR in C/EBP knockout mouse embryo fibroblasts (Wu et al. 1999
) or in NIH-3T3 fibroblasts that are defective for C/EBP
expression (El-Jack et al. 1999
). Under potent
adipogenic conditions, including PPAR ligand supplement, fibroblasts
in either case formed characteristic lipid droplets and expressed many
genes associated with adipocyte differentiation. However, these
fibroblasts are not responsive to insulin regarding glucose uptake
(Fig. 3)
. Rescue of this defect with coexpression of C/EBP clearly
demonstrates synergy among these adipogenic transcription factors
within a program of events involving many proteins necessary for the
complex process of insulin sensitivity. Although the precise defect
remains under investigation, positive cooperation between C/EBP and
PPAR appears to be obligatory for this important aspect of adipocyte
function.
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Nutritional regulation of PPAR in lipid and glucose homeostasis
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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as a major component of
the transcriptional cascade leading to adipogenesis. Recent
investigations have broadened our appreciation of PPAR as a
potential physiologic sensor of lipid levels, linking fatty acids and
other lipid-related molecules to glucose and lipid homeostasis
(Fig. 4
). Ligands for this nuclear hormone receptor include the naturally
occurring eicosanoid, 15-deoxy prostaglandin J2
(Forman et al. 1995
) and a group of synthetic compounds
(the TZDs, e.g., troglitazone, rosiglitazone) that have been used in
the treatment of adult onset (Type II) diabetes (Lehmann et al. 1995
). Several long-chain polyunsaturated fatty acids
(PUFA) bind to PPAR in vitro and can stimulate lipid-lowering
and enhanced insulin sensitivity effects similar to those reported for
synthetic PPAR ligands (Xu et al. 1999
). Albeit
unproven, it is hypothesized that various PUFAs and/or prostaglandins
are likely to function as PPAR ligands in vivo, linking these lipid
metabolites to gene expression mediating lipid homeostasis.
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also plays a regulatory role in
lipid homeostasis in other cell types. Recent evidence demonstrating
that PPAR is expressed significantly in mammary and intestinal
epithelia (Lefebvre et al. 1999
, Mueller et al. 1998
) and two classes of macrophages (Jiang et al. 1998a
, Ricote et al. 1998
) provides additional
support for a general role for PPAR in lipid homeostasis. This
notion is best exemplified by studies examining the development of
atherosclerotic lesions within the arterial wall that contain
cholesterol-laden macrophages known as foam cells. The uptake of
oxidized LDL (oxLDL) through scavenger receptors has been shown to
enhance the expression of PPAR within these macrophages (Nagy et al. 1998
, Tontonoz et al. 1998
). Results from
recent studies have provided evidence leading to the hypothesis that
oxidized lipid components of oxLDL, 9-HODE and 13-HODE, can function as
endogenous activators and ligands of PPAR (Fig. 4)
, thus providing a
molecular mechanism linking oxLDL to the transcriptional control of
macrophage gene expression. One target of PPAR in these cells is the
scavenger receptor, CD36, which establishes a positive feedback loop
that increases the uptake of oxLDL and metabolites that function to
enhance PPAR transcriptional activity (Tontonoz et al. 1998
). Although a role for PPAR in mediating lipid
metabolism in macrophages is supported by these findings, it remains to
be determined whether activation by oxidized fatty acids plays a
significant role in PPAR-mediated processes in other tissues. |
Differential effects of PPAR ligands on transcriptional activity
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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in nonadipose tissues alludes to the
possibility of diversified function based on tissue-specific
expression of coactivators and corepressors and/or the availability of
selective ligands that may alter the transcriptional activity and/or
targets of PPAR. In support of this notion, PPAR-coactivators,
PGC-1 and PGC-2, have been reported, with tissue distributions
restricted to brown and white adipose tissue, respectively
(Castillo et al. 1999
, Puigserver et al. 1998
). Although these molecules possess domains unconventional
to other known coactivators, they interact with PPAR; when they are
expressed ectopically, they have the ability to enhance the
differentiation of the respective adipose tissue. Therefore, functions
for PPAR that are tissue specific may be controlled at the level of
coactivator distribution.
The function of PPAR in different tissues may also be controlled by
the availability of different ligands produced in a tissue-specific
fashion. Furthermore, it is plausible that PPAR functions within a
specific tissue may be altered on the basis of availability of
potential ligands, which in turn direct transcriptional activity toward
the appropriate homeostatic conditions. By way of illustration,
differentiation of 3T3-L1 preadipocytes results in a coordinate
increase in both adipsin and aP2 mRNA accumulation over the course of
4–6 d after induction of differentiation with a combination of mitogen
and hormonal agents (Fig. 5A
). The fact that these preadipocytes do not require exogenous ligands
for PPAR for differentiation has led to the notion that these cells
are capable of synthesizing an endogenous ligand. Interestingly,
differentiation of these preadipocytes in the presence of the synthetic
PPAR ligand, troglitazone, results in a unexpected repression of
adipsin in a ligand dose-dependent fashion (Fig. 5B
).
Although the effect of troglitazone in enhancing PPAR activity can
be predicted by the increase in aP2 expression, it is clear that the
same PPAR ligand can result in a differential profile of adipogenic
gene expression. Others have reported the synthesis of a ligand for
PPAR that binds tightly to the receptor domain and functions as a
partial agonist for PPAR transactivation (Oberfield et al. 1999
). Interestingly, this compound was found to be a potent
antagonist of adipocyte differentiation. Collectively, these data
suggest that the molecule residing in the ligand-binding pocket of
PPAR can have a dramatic effect on the function of this nuclear
hormone receptor.
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Prospective |
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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and C/EBP as the most prominent transcription factors mediating
adipogenesis. The direct mechanism whereby these
trans-acting factors, independently and/or cooperatively,
activate gene expression important for adipocyte function and their
roles in regulating the expression of intermediary transcription
factors will undoubtedly represent a focus for future investigations.
The increasing list of adipocyte functions beyond the storage of
triglycerides will require an evolving definition of adipocyte
differentiation and, consequently, the cascade of transcriptional
events mediating adipogenesis. Analysis of the mechanisms whereby
hormonal and nutritional signaling impinges on the adipogenic
transcription factors will provide an important link between the
cellular environment and regulation of gene expression important for
glucose and lipid homeostasis.
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FOOTNOTES |
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2 Supported by grants from the Boston Obesity
Nutrition Research Center (DK46200) to R.F.M. and National Institutes
of Health (DK51586) to S.R.F.
4 Abbreviations used: ADD1, adipocyte
determination- and differentiation-dependent factor 1; C-EBP,
CCAAT/enhancer binding protein-; JAK, Janus kinases;
oxLDL, oxidized LDL; PPAR, peroxisome proliferator–activated
receptor-; PUFA, polyunsaturated fatty acids; RXR, retinoid X
receptor; SREBP, sterol regulatory element binding proteins; STAT,
signal transducers and activators of transcription; TZD,
thiazolidinediones.
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TOPABSTRACTPleiotropic functions of the...Transcription factors regulating...Cascade of transcriptional...Nutritional regulation of...Differential effects of...ProspectiveREFERENCES |
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