Báo cáo khoa học: Mechanisms of obesity and related pathologies: Transcriptional control of adipose tissue development pdf

MINIREVIEW
Mechanisms of obesity and related pathologies:
Transcriptional control of adipose tissue development
Cecile Vernochet, Sidney B. Peres and Stephen R. Farmer
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
Introduction
Obesity is a worldwide epidemic and a major contribu-
tor to the development of a group of potentially
life-threatening conditions referred to as the metabolic
syndrome. This syndrome groups together several
pathologies that can coexist, including insulin resis-
tance, type II diabetes, dyslipidemia, cardiovascular
disease, inflammation and some cancers, and all have a
strong association with intra-abdominal adipose tissue
mass [1]. Consequently, obesity has a significant cost
on the well being of society because the incidence of
these diseases is expected to double by the year 2030
and the associated healthcare expenditure will be
> $100 billion in the USA alone [2,3]. The increased
incidence of obesity, particularly in Western society, is
considered to be the result of a change in lifestyle (i.e.
less exercise) and eating habits (i.e. quantity and
quality of food), which leads directly to an increase in
adipose tissue mass and a disturbance of metabolism.
A principal function of the adipose tissue is to store
consumed dietary energy in the form of triglycerides
within specialized organelles referred to as lipid drop-
lets in adipocytes. This stored energy can be mobilized
by activating lipolysis in response to the needs of the
organism to supply fuels and nutrients to other organs.
Adipose tissue also contributes to whole-body homeo-

stasis as an endocrine organ secreting a multitude of
Keywords
brown adipose tissue; obesity;
progenitors; PPAR gamma;
white adipose tissue
Correspondence
S. R. Farmer, Department of Biochemistry,
Boston University School of Medicine,
715 Albany Street, Boston, MA 02118,
USA
Fax: +1 617 638 5339
Tel: +1 617 638 4186
E-mail:
(Received 25 March 2009, revised 5 August
2009, accepted 13 August 2009)
doi:10.1111/j.1742-4658.2009.07302.x
Obesity and its associated disorders, including diabetes and cardiovascular
disease, have now reached epidemic proportions in the Western world,
resulting in dramatic increases in healthcare costs. Understanding the pro-
cesses and metabolic perturbations that contribute to the expansion of adi-
pose depots accompanying obesity is central to the development of
appropriate therapeutic strategies. This minireview focuses on a discussion
of the recent identification of molecular mechanisms controlling the devel-
opment and function of adipose tissues, as well as how these mechanisms
contribute to the regulation of energy balance in mammals.
Abbreviations
BAT, brown adipose tissue; BMPs, bone morphogenetic proteins; C ⁄ EBP, CCAAT-enhancer-binding proteins; CtBP, C-terminal-binding
protein; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; PGC1, PPARc coactivator-1; PPAR, peroxisome
proliferator-activated receptor; PRDM16, PR domain containing 16; SRC-1, steroid receptor coactivator-1; SVF, stromal vascular fraction;
TZD, thiazolidinedione; UCP-1, uncoupling protein-1; WAT, white adipose tissue.

FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5729
cytokines and hormones. An excess of food intake can
increase fat mass and disrupt energy balance. Recent
studies suggest that enlarged adipose tissue suffers
from a variety of stresses, most likely as a result of
lipotoxicity, hypoxia and low-grade chronic inflamma-
tion [4]. The fat tissue responds to stress by repro-
gramming its normal functions, comprising a change
in the level and nature of the secreted adipokines and
mobilization of stored lipids that are released into the
circulation as free fatty acids, leading to lipotoxicity
within other metabolic tissues. These responses are
further exacerbated by the proliferation and differenti-
ation of preadipocytes and possibly progenitor cells
within adipose depots providing more adipocytes for
hypertrophic expansion. This review discusses the
mechanisms controlling the formation and function of
adipose tissue and how these processes might be
altered by various therapeutic interventions to correct
the energy imbalances resulting from obesity.
Location and function of the white and
brown depots
Adipose tissue is the most abundant tissue in humans,
representing approximately 10–29% of body weight. It
is found in a multitude of locations and consists of
two major forms: white adipose tissue (WAT) and
brown adipose tissue (BAT). WAT is the main site for
the storage of energy in the form of triglycerides
located in large lipid droplets that occupy most of
intracellular space of the many adipocytes distributed

throughout the tissue. BAT, on the other hand, usually
consumes energy to produce heat by catabolizing lip-
ids; consequently, brown adipocytes store fewer trigly-
cerides within small lipid droplets. WAT is mainly
divided into two groups with distinct functions: sub-
cutaneous (buttocks, thighs and abdomen) and
intra-abdominal ⁄ visceral fat (omentum, intestines and
perirenal areas) [5]. Each of these depots express
important differences in their function stemming from
a different pattern of gene expression [6]. Such func-
tional differences appear to contribute to their particu-
lar involvement in the development of the various
pathologies associated with obesity. Specifically, lipid
turnover in visceral WAT is faster than that in subcu-
taneous compartments, thereby allowing a constant
release of non-esterified fatty acids into the circulation.
This turnover results from a high catecholamine-stimu-
lated lipolysis and a reduction in the response to the
anti-lipolytic activity of insulin. Additionally, visceral
and subcutaneous adipose tissues secrete different
patterns of adipokines and inflammatory cytokines in
which the visceral depot tends to be significantly more
inflammatory than the subcutaneous depot [7]. It is
likely that the expansion of a particular WAT depot
will predict the metabolic outcome of an individual as
they become obese. Indeed, it is well known that not
all obese individuals with the same body mass index
become insulin resistant or develop type 2 diabetes or
cardiovascular disease. Obese (i.e. metabolically
healthy obese) subjects who usually accumulate the

excess fat subcutaneously in the lower body (gynoid
type of obesity) are metabolically healthy. However,
other individuals (i.e. metabolically obese normal
weight) with near normal body mass index are meta-
bolically obese because they express many of the
abnormalities associated with the metabolic syndrome.
In some less common cases, individuals with lipodys-
trophy, which results in a partial to almost complete
loss of body fat, are highly prone to developing insulin
resistance and associated diseases. There is a dearth of
knowledge concerning the genetics and associated
molecular mechanisms giving rise to such extremes of
fat deposition within the population. Consequently,
attempts to understand these processes will undoubt-
edly contribute to strategies aiming to combat obesity
and related dislipidemias.
Much of our understanding of the involvement of
adipose tissue in the metabolic syndrome has focused
on white depots, as outlined above. Recent observa-
tions of patients undergoing screening for various
cancers have identified BAT in adult humans [8] that
also likely influences energy balance and therefore
contributes to the development of metabolic diseases.
BAT is significantly more vascularized than WAT,
and brown adipocytes contain abundant mitochon-
dria to facilitate the catabolism of lipids through
mitochondria-based b-oxidation; these features
contribute to the red–brown color of the depot [5].
In rodents, BAT is mainly concentrated within the
interscapular regions throughout adult life, whereas,

in humans, it exists within these regions during fetal
and neonatal periods of development. Indeed, until
the recent discovery of BAT in adult humans, it was
assumed that the absence of interscapular BAT
meant that adults lack brown fat. However, the use
of [
18
F]-2-fluoro-d-deoxy-d-glucose positron emission
tomography for metastatic cancer screening has iden-
tified metabolically active BAT depots in the cervical,
supraclavicular, axillary and paravertebral regions of
adult humans [8–11]. BAT appears to be more fre-
quent in women than in men, is inversely correlated
with the body mass index, and can be activated by
cold exposure. Even though the contribution of
BAT to adult physiology is still unclear, the recent
discovery that BAT exists in a significant amount in
Control of adipose tissue development C. Vernochet et al.
5730 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS
humans should stimulate renewed interest in under-
standing its formation and function.
Differentiation of white and brown
preadipocytes
Changes in adipose tissue mass as a result of genetic
and environmental factors involve both hyperplasia
(i.e. an increase in adipocyte number) and hypertrophy
(i.e. an expansion of adipocyte volume as a result of
the accumulation of lipids). Consequently, knowledge
of the origin and molecular control of adipocyte
progenitor commitment is important for our under-

standing of what controls the expansion of fat mass in
different individuals. Moreover, it is also important to
understand the origins of each of the different white
and brown depots because it appears that not all
depots are equal as far as their involvement in the
metabolic syndrome.
White and brown adipocytes form during the differ-
entiation of white or brown preadipocytes arising from
mesenchymal stem cells located at different sites in the
developing organism. Preadipocyte differentiation (adi-
pogenesis) is regulated by a plethora of extracellular
and intracellular signaling molecules and transcription
factors that are common to both white and brown
lineages, as well as specific to a particular type of prea-
dipocyte [12]. Both white and brown adipogenesis is
initiated by the activation of a cascade of transcription
factors whose principal function is to induce the
expression of peroxisome proliferator-activated recep-
tor (PPAR)c and CCAAT-enhancer-binding protein
(C ⁄ EBP)a, which are the master regulators of genes
coding for the shared functions of white and brown
adipocytes, including lipid and glucose metabolism,
mitochondrial biogenesis and the production of adipo-
kines [13–15]. PPARc is a member of the nuclear
hormone receptor superfamily whose transcriptional
activity is regulated by binding to appropriate ligands,
which includes derivatives of fatty acids and synthetic
lipophilic molecules employed as potent therapeutics
for the treatment of insulin resistance, most notably
the thiazolidinediones (TZDs), rosiglitazone and piog-

litazone [16]. CEBPa cooperates with PPARc to elicit
a positive-feedback loop that maintains the expression
of both genes in the mature adipocyte and facilitates
the expression of multiple proteins regulating insulin
sensitivity, including the insulin-dependent glucose
transporter GLUT4 and the insulin-sensitizing hor-
mone, adiponectin [13]. Indeed, two recent studies
demonstrate that the mechanisms by which PPARc
and C ⁄ EBPs (C ⁄ EBPb and C ⁄ EBPa) cooperatively
orchestrate adipocyte formation and function involve
the binding to a large (> 3000) overlapping set of
target genes [17,18].
The formation of brown adipocytes requires the
expression of an additional set of transcriptional regu-
lators that are absent or expressed at very low levels in
white preadipocytes ⁄ adipocytes. These include two
coregulators of transcription factors, a zinc finger pro-
tein, PR domain containing 16 (PRDM16) and PPARc
coactivator-1 (PGC-1)a [19,20]. Another member of
the PGC-1 family, PGC-1b, is also expressed in white
adipocytes, but appears to provide a function in asso-
ciation with PGC-1a that is required for brown cell
formation. The PGC1 transcriptional coactivators are
major regulators of many aspects of oxidative metabo-
lism, including mitochondrial biogenesis and respira-
tion in oxidative tissues, such as cardiac and skeletal
muscle and the liver, as well as brown adipocytes [21].
Mice deficient for PGC-1a expression are cold sensitive
partly because of absence of uncoupling protein-1
(UCP-1), a proton transporter in brown adipocyte

mitochondria that uncouples electron transport from
ATP production, allowing the energy to dissipate as
heat. Brown preadipocytes that lack PGC-1a are capa-
ble of differentiating into brown fat cells as defined by
enhanced mitochondrial biogenesis and the production
of brown cell markers (i.e UCP-1), but they cannot
induce thermogenesis in response to cAMP. Brown
preadipocytes lacking both PGC-1a and PGC-1b are
capable of forming adipocytes based on the accumula-
tion of lipid droplets and the expression of genes com-
mon to both white and brown fat function. They do
not, however, produce brown-selective genes involved
in mitochondrial biogenesis and function [22]. PGC-1b
is expressed in white adipocytes and its absence might
prevent the expression of some unknown function of
white adipocytes. PGC-1 coactivators appear to regu-
late the expression of genes involved in mitochondrial
biogenesis and thermogenesis by coactivating several
different transcription factors, including nuclear respi-
ratory factors 1 and 2, PPARc and estrogen-related
receptora.
PRDM16 is highly expressed in brown adipocytes
and absent from white adipocytes. It is required for
brown adipocyte differentiation but is also expressed
in other tissues [19]. Ectopic expression of PRDM16 in
white adipocytes in culture or white depots in mice
induces a program of gene expression, as well as mito-
chondrial biogenesis and lipid metabolism consistent
with the brown phenotype. Similarly, its knockdown in
brown fat cells ablates their brown characteristics.

PRDM16 appears to function by directing the PGC-1
coactivators to their target transcription factors
docked on promoters ⁄ enhancers of genes controlling
C. Vernochet et al. Control of adipose tissue development
FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5731
the brown phenotype. Additionally, other studies sug-
gest that PRDM16 also functions to repress select
white adipocyte genes that are produced at very low
levels in brown adipocytes [23]. Earlier studies have
also suggested a role for the p160 family of coactiva-
tors [steroid receptor coactivator-1 (SRC-1) and tran-
scriptional intermediary factor-2 (TIF-2)] in regulating
brown versus white adipocyte formation [24]. The data
obtained in these studies are consistent with a role for
SRC-1 in coactivating PPARc ⁄ PGC-1a to enhance the
expression of brown target genes most notably UCP-1.
Transcriptional intermediary factor-2 appears to atten-
uate the activity of SRC-1 and thereby favors a white
phenotype. It is therefore likely that mechanisms
directing the differentiation of white or brown prea-
dipocytes will produce the appropriate levels of these
two coactivators in accordance with the eventual
phenotype.
It appears that the maintenance of the white pheno-
type involves an active repression of brown genes in
addition to the lack of the coactivators PGC-1a and
PRDM16. Most notably, RIP140 (a ligand-dependent
repressor of nuclear receptors), comprising a global
negative regulator of genes controlling mitochondrial
biogenesis, is highly expressed in WAT compared to

BAT [25]. Knockout of RIP140 in mice leads to a lean
phenotype as a result of a 70% reduction in total body
fat present in the white depots but with the same num-
ber of smaller adipocytes relative to controls and no
change in food consumption [26]. The mice are also
resistant to diet-induced obesity and appear to oxidize
the consumed fat rather than storing it. Indeed, the
suppression of RIP140 in white adipocytes by small
interfering RNAs leads to a significantly enhanced
expression of genes coding for mitochondrial functions
such as thermogenesis and the b-oxidation of lipids
[27,28]. The gene silencing activity of RIP140 involves
an association with additional corepressors, including
the NADH-dependent C-terminal-binding proteins
(CtBPs) [25], which have recently been shown to facili-
tate the repressive activity of PRDM16 [23] in brown
adipocytes as well as that of C ⁄ EBPa in white adipo-
cytes [29]. The precise role of CtBPs in regulating
brown versus white adipocyte formation, however,
remains unclear.
Other regulators of white versus brown adipogenesis
include the retinoblastoma protein Rb and its pocket
protein family member p107 [30,31]. The suggestion
that pocket proteins might negatively regulate brown
adipocyte formation came from the fact that SV40
large T antigen, which binds to Rb, promotes the
formation of brown adipocytes subsequent to its
expression in white preadipocytes. Indeed, the disrup-
tion of the Rb gene in white preadipocytes facilitates
their differentiation into brown adipocytes, in part by

enhancing PGC-1a expression and activity. Addition-
ally, p107
) ⁄ )
mice contain a significantly reduced white
fat mass with no change in the mass of the interscapu-
lar brown depot. The adipocytes present in the
p107
) ⁄ )
WAT contain smaller lipid droplets and more
mitochondria, and express higher levels of UCP-1 and
PGC-1a and lower levels of Rb. The role of these
various transcription factors and nuclear factors is
highlighted in Fig. 1.
Developmental origin of WAT and BAT
Fat depots are composed principally of two compart-
ments, the stromal vascular fraction (SVF) and adipo-
cytes filled with lipids. The SVF contains adipocyte
precursors, preadipocytes, vascular cells such as endo-
thelial and pericytes, as well as immune cells. The SVF
is considered to be a source of adipocyte precursors
because of the presence of cells within this fraction
with the capacity to differentiate into adipocytes
in vitro. Until recently, white and brown adipocytes
were believed to arise from a common mesodermal
progenitor, although recent studies employing lineage
tracer techniques have started to identify progenitors
specific for white versus brown depots. Some white
adipocytes come from the neural crest, which derive
from the neuroectoderm and can migrate to different
regions during embryonic development. In vivo,it

appears that only adipocytes in the cephalic region
derive from the cranial neural crest [32] and that the
other major depots have a separate developmental
origin. It is very likely that the subcutaneous versus
visceral white depots have distinct origins because they
each express a unique pattern of developmental genes.
Specifically, subcutaneous fat in both rodents and
humans displays higher levels of En1 (engrailed 1),
Shox2 and sfrp2, whereas intra-abdominal adipocytes
express higher levels of Nr2f1 (COUP-TFI), HoxA5
and HoxC8 [6]. Recent studies have also highlighted
the role of pericytes as progenitors of white adipocytes.
Pericytes derived from the sclerotome (mesodermal
origin) are an integral part of the microvasculature
and are involved in a number of different processes,
including angiogenesis and vasculogenesis [33]. Their
source as potential stem cells for adipocytes in vitro
and in vivo, as well as chondrocytes, osteoblasts and
smooth muscle cells, has already been reported [34,35].
A recent study by Graff and colleagues [36] employing
the upstream region of the PPARc gene to direct the
expression of reporter genes in a series of elegant
in vivo fate mapping investigations demonstrated that
Control of adipose tissue development C. Vernochet et al.
5732 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS
some white adipocytes arise from the mural compart-
ment of blood vessels supplying adipose depots. Specif-
ically, Graff and colleagues [36] generated a transgenic
mouse in which the upstream region of the PPARc
gene containing the promoters for both PPARc1 and

PPARc2 was used to direct the expression of a doxicy-
cline-repressible transactivator (Tet-off tTA). Using
this mouse (PPARc-tTA), two further strains of trans-
genics were generated. In one case (LacZ mouse), two
additional alleles corresponding to a tTA-responsive
Cre recombinase (TRE-Cre) and an allele (ROSA26-
flox-stop-flox-lacZ) that indelibly expresses LacZ
(b-galactosidase) in response to Cre activity were intro-
duced. The generation of the other mouse [green
fluorescent protein (GFP) mouse] involved the intro-
duction of a TRE-H2B-GFP allele into the PPARc-
tTA background to create a proliferation sensitive
GFP reporter of PPAR c promoter activity. Conse-
quently, the activation of the adipogenic-specific
PPARc promoters during the development of adipo-
cyte progenitor cells in the LacZ-mouse produced Cre
that indelibly marked the cells with LacZ. LacZ
expression can be repressed by doxicycline. If doxicy-
cline was given to the mice after the expression of the
PPARc-Cre gene, then the marked cells continued to
produce LacZ because of the indelible nature of the
system (ROSA26-flox-stop-flox-lacZ). In the other
GFP mouse, activation of the PPARc promoters
induced tTA, leading to production of GFP. Exposure
to doxicycline after the initial developmental activation
of the transgenic PPARc gene blocked GFP expression
and the cells lost their GFP through dilution accompa-
nying proliferation. If the marked cells became quies-
cent, they continued to produce GFP and remained
marked. To analyze the rapid and extensive expansion

of the adipose lineage during the first postnatal
30 days (P30), Graff and colleagues [36] treated the
LacZ-mice with doxicycline at different days during
this developmental period. They observed homoge-
neous lacZ expression in P30 white adipose depots that
was not significantly diminished even when doxicycline
was given to the mice during the first few postnatal
days. These data suggest strongly that the majority of
P30 adipocytes arise from a pre-existing, perinatal pool
of PPARc-expressing cells (either adipocytes or prolif-
erating progenitors). To determine whether these pre-
existing cells were proliferating progenitors, the GFP
mice were exposed to doxicycline between days P2 and
P30 or allowed to mature to day p30 without any
exposure. The adipose depots of the untreated mice
expressed GFP, whereas those mice that were treated
with doxicycline as early as P2 showed a marked
reduction in GFP expression in both adipose depots
and adipocytes. Taken together, the data obtained by
Graff and colleagues [36] show that a pool of white
adipocyte precursors is established perinatally and can
proliferate. Additional studies also revealed that a
progenitor pool continues to exist into adulthood for
self-renewal during growth. Furthermore, fluorescence-
activated cell sorting (FACS) isolation of the
GFP-expressing progenitor cells from the stromal vas-
cular fraction of adipose depots showed an adipogenic
White Brown
PRDM16 pR b
C/EB P β

C/EB P δ
Ligands PGC1 α
α
TIF2
p107
RX R
PP AR γ
γ
PRDM16
C/EBP α
α
PGC1 β
β
SRC1
RIP140
TIF2
RX R α
PP AR
PRDM16
CtBP1/ 2 CtBP1/ 2
C/EBP α
α
C/EBP α
α
TZD
Mitochondria
bi i
Mitochondria
bi
TZD

« White » « White »
Lipogenesi s
Insulin sensitivity
Adipokine s
ogene s i s
Thermogenesis (UCP1)
Lipids β−oxidation
biiogenesis
Thermogenesis (UCP1)
Lipids β−oxidation
gene s gene s
Fig. 1. Transcription factors and nuclear reg-
ulators controlling the expression of genes
responsible for white versus brown adipo-
cytes. White and brown adipocyte differenti-
ation shares a common transcription
cascade that leads to a lipogenic ⁄ lipolysis
function and insulin sensitivity (central cas-
cade). PRDM16, PGC1a and PGC1b induce
the brown phenotype (mitochondria biogen-
esis and thermogenic function) within brown
adipocytes (right), whereas these functions
are repressed by RIP140 and Rb within
white adipocytes (left). On the other hand,
CtBP1 ⁄ 2 represses a set of genes
expressed at a higher level in white adipo-
cytes (called ‘white’ genes) by interacting
with PRDM16 in brown adipocytes (right)
and with C ⁄ EBPa in white adipocytes upon
TZD treatment (left).

C. Vernochet et al. Control of adipose tissue development
FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5733
potential in vitro. This same pool expressed a set of
markers consistent with them belonging to the mural
cell compartment including Sca-1, CD34, smooth mus-
cle actin and platelet-derived growth factor b. These
progenitors only existed in the vasculature of adipose
tissue, and not in other organs, demonstrating that this
population of mural cells is specifically committed to
adipocyte lineage.
A complementary series of studies performed by
Friedman and colleagues [37] identified a subpopula-
tion of early adipocyte progenitor cells (Lin):
CD29+:CD34+:Sca-1+:CD24+) resident in the
SVF of adult WAT with a significantly enhanced adi-
pogenic potential over other cells isolated from the
SVF. Engraftment of CD24+ cells is sufficient to
restore a functional white depot in lipodystrophic
mice and, in doing so, is sufficient to restore blood
glucose levels to those of wild-type mice. These inves-
tigators also isolated CD24+ cells from a transgenic
mouse expressing a luciferase cDNA under the control
of the adipocyte-specific leptin promoter. By visualiz-
ing luciferase activity, they could monitor the develop-
ment of newly-formed adipose tissue without invasive
surgery. These CD24+ precursors failed to differenti-
ate when engrafted into WAT pad of wild-type mice
fed a normal diet. By contrast, when recipient wild-
type mice were fed a high fat diet, luciferase activity
was detected in three out of eight mice, suggesting

that the local environment facilitates the recruitment
and differentiation of the newly forming CD24+
adipocyte population. Interestingly, Friedman and
colleagues. [37] have identified two populations of
cells by FACS within the SVF depot that express dif-
ferent levels of adipogenic potential based on the
in vitro and in vivo expression of different adipocyte
genes. The presence of at least two different popula-
tions of adipocyte precursors within a white depot has
also been reported in others studies, including those
conducted in young donors in which the populations
within the same SFV were dissociated from each
other by their different adhesion properties. Even
though the fast- and slow-adherent cells showed
adipocyte differentiation capacity ex vivo, the fast-
adherent one showed higher proliferation properties
and potential therapeutic values [38,39]. Identifying
precursors by FACS, giving them an identity card,
and subsequently sorting them out, provides a power-
ful tool for studying their function and properties
with respect to therapeutic purposes.
In the case of brown adipose development, Timmons
et al. [40] reported that brown adipocyte precursors
express a pattern of gene expression that overlaps with
cells of myogenic origin. Recent fate mapping studies
using the myogenic-specific promoter myf5 as the line-
age tracer demonstrated that brown adipocytes and
skeletal muscle share a common myf5
+
progenitor

that originates from dermomyotome [41]. Additionally,
studies by Atit et al. [42] showed that some interscapu-
lar brown fat bundles originate from cells of the
dermomyotome that express En1. This close relation-
ship between the myocyte and the brown adipocyte is
consistent with both cell types expressing a common
set of phenotypic characteristics, including specializa-
tion for lipid catabolism requiring abundant mitochon-
dria. Moreover, the dermomyotomal origins of brown
adipocytes clearly reveal that they have a distinct
developmental origin that is separate from the scle-
rotomal (pericytes) origin of white adipocytes. It is
also interesting that brown adipocytes found within
white depots do not appear to arise from myf5-con-
taining progenitors [41]. These brown adipocytes might
develop by some unknown reprogramming of the
white progenitors or transdifferentiation of white prea-
dipocytes into brown adipocytes. The various lineages
that give rise to the different adipose tissues are shown
in Fig. 2.
As descriptive as these fate mapping studies may be,
they have the potential to provide powerful tools for
identifying the genes and signaling pathways responsi-
ble for the acquisition of different phenotypes in sub-
cutaneous versus visceral depots. For example, the
expansion of the visceral fat depot appears to be a
more potent trigger for development of the metabolic
syndrome than expansion of the subcutaneous depot.
Understanding the mechanisms by which visceral
adipocytes can express a more subcutaneous or brown

phenotype should aid in the development of anti-
obesity therapeutics.
Recent lineage tracing studies suggest that both white
and brown adipocytes originate from mesenchymal stem
cells arising at a very early stage of development of the
epithelial somite. A critical event within the somite is an
epithelial–mesenchymal transition that facilitates forma-
tion of the sclerotome and the dermomyotome ⁄
myotome. Brown adipocytes likely arise from myf5
+
progenitor cells of the dermomyotome that also produce
skeletal muscle, whereas white adipocytes arise from
mural cells (pericytes) that originate in the sclerotome.
The development of mesodermal tissues is controlled
by a conserved set of embryonic signaling pathways,
including bone morphogenetic proteins (BMPs), wing-
less (Wnt), and nodal and fibroblast growth factors [6].
Recent studies suggest that these pathways might have a
role in directing the formation of WAT and BAT during
development. The most notable of these adipogenic
effectors are members of the BMP family of transform-
Control of adipose tissue development C. Vernochet et al.
5734 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS
ing growth factors. Many mouse models lacking either
ligands, receptors or components of BMP signaling have
been developed that show defects in mesodermal forma-
tion [43]. Certains BMPs, in particular BMP2 and
BMP4, enhance white adipogenesis in the presence of
select hormones [44], whereas BMP7 appears to play a
key role in the determination of BAT [45]. BMP7 knock-

out embryos show a reduced brown fat pad mass and
almost no UCP-1 expression. The adenoviral-mediated
expression of BMP7 in mice results in a specific increase
in brown but not white fat, leading to weight loss and an
increase in energy expenditure [45].
Adipose tissue remodeling and the
redistribution of lipids between the
different white and brown depots
A potential strategy for combating the negative health
consequences of too much stored lipid in the visceral
adipose depots is to redirect storage to the subcutane-
ous compartment. Additionally, reprogramming vis-
ceral depot gene expression to resemble the
subcutaneous depot might also reduce pathologies
associated with the enlarged visceral fat mass, without
necessarily needing to mobilize the stored lipid. Indeed,
the activation of PPARc in vivo by treatment of
humans or mice with the TZD family of PPARc
ligands causes a redistribution of lipid from visceral to
subcutaneous fat [46]. A preferential increase in glu-
cose uptake and intracellular metabolism in subcutane-
ous fat contributes to the redistribution of triglycerides
from visceral to subcutaneous in response to PPARc
ligands [47]. A recent study in rats treated with the
non-TZD PPARc agonist demonstrated that the tri-
glyceride-derived lipid uptake and lipoprotein lipase
activity in interscapular brown and subcutaneous
inguinal fat depots are higher than those rates deter-
mined in visceral tissues [48]. Thus, the activation of
PPARc increases the metabolic activity of subcutane-

ous depots.
Another anti-obesity therapy would be to enhance
the contribution of BAT to overall lipid metabolism.
This could involve the redirection of consumed energy
such as glucose and lipids to already existing BAT for
catabolism rather than anabolism in white depots. This
might require the selective activation of glucose and
lipid metabolism in brown adipocytes. In this regard,
recent studies have demonstrated that rosiglitazone
enhances rat BAT lipogenesis from glucose without
altering glucose uptake [49]. The most beneficial strat-
egy, however, would be to increase the amount of
BAT relative to WAT. It is well known that brown
adipocytes can emerge within white depots in response
to a variety of stimuli, including catecholamines, cold
exposure, diet and PPARc ligands [14,50], although
whether this adaptive response is sufficient to signifi-
cantly alter energy balance in obese individuals is
unclear. The recent discovery of BAT in adult humans
presents investigators with the new challenge of how
to increase its mass and ⁄ or activity as a part of an
anti-obesity therapy. Additional knowledge of the
molecular mechanisms controlling the formation of all
adipose depots will contribute to the goal of combat-
ing obesity and its associated disorders.
Sclerotome
PPARγ

+
Neural crest

sox10 +
Other
MSC?
Dermomyotome
Myf 5 +
Other
MSC?
?
White progenitors
Brown progenitors
Pericyte
PDFβ

+, CD34 +
Myoblast
Nr2f1, HoxA5,
HoxC8
En1, Shox2,

sfrp2
?
Subcutaneous
WAT
Visceral
WAT
Facial WAT
BAT
Muscle
Brown-like
adipocyte

?
Myf 5 - Myf 5 +
Fig. 2. Putative stem cell lineages that give
rise to white and brown adipose depots,
highlighting the complexity of the origins of
adipose tissues. A common precursor cell
expressing myf5
+
gives rise to both brown
adipocytes and skeletal muscle. Brown
adipocytes that can arise within white adi-
pose depots are myf5
)
, demonstrating that
a bridge between the white and brown line-
age is possible either during the progenitor
phase or at the differentiated phase. On the
other hand, different white depot progeni-
tors (visceral and subcutaneous) express dif-
ferent developmental genes and some facial
WAT can originate from the neural crest.
C. Vernochet et al. Control of adipose tissue development
FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5735
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