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

Abbreviations BAT, brown adipose tissue; BMPs, bone morphogenetic proteins; C⁄ EBP, CCAAT-enhancer-binding proteins; CtBP, C-terminal-binding protein; FACS, fluorescence-activated cell s

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: farmer@biochem.bumc.bu.edu

(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.

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 [18F]-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

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

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

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 PPARc 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

TIF2 p107

RX R PP AR γ PRDM16

C/EBP α

PGC1 β

SRC1

RIP140

TIF2 RX R α PP AR PRDM16

CtBP1/ 2 CtBP1/ 2

C/EBP α

C/EBP 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).

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 aprea-dipocytes 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-ing growth factors Many mouse models lacktransform-ing 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

PPAR γ + Neural crest

sox10 +

Other MSC?

Dermomyotome

Myf 5 +

Other MSC?

? White progenitors Brown progenitors

Pericyte PDF β +, CD34 +

Myoblast

Nr2f1, HoxA5, HoxC8 En1, Shox2, sfrp2

?

Subcutaneous WAT Visceral

WAT

adipocyte

?

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.

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