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Biochimica et Biophysica Acta xxx (2013) xxx–xxx
BBADIS-63734; No. of pages: 12; 4C: 2, 6, 7, 9
Contents lists available at SciVerse ScienceDirect
Biochimica et Bi
e ls
being spared or even expanding [2,3].With aworldwide obesity epidemic
well underway, the study of adipose tissue growth, distribution, and reg-
ulation is a major research focus. Yet the developmental origins of fat, the
determinants of body fat distribution, and the signalingmechanisms that
control fat growth remain poorly defined.
2. Adipose tissue is complex and heterogeneous
According to [4],WAT depots in rodents include the anterior subcutane-
ous WATs (asWATs) including interscapular and axillary WAT (located
in the scapular region), inguinalWAT (ingWAT; attached dorsally along
the pelvis to the thigh of the hindlimb), perigonadal WAT (pgWAT;
surrounding the uterus and ovaries in females and the epididymis
and testes in males), retroperitoneal WAT (rWAT; located within the
abdominal cavity along the dorsal wall of the abdomen behind the kid-
ney but not attached to the kidney ormixedwith perirenal brown fat),
In mammals, fat is typically classified by
ance as being either white adipose tissue (W
☆ This article is part of a Special Issue entitled: Modulat
and Disease.
⁎ Corresponding author. Tel.: +1 508 856 8064.
E-mail address: david.guertin@umassmed.edu (D.A.
0925-4439/$ – see front matter © 2013 Elsevier B.V. All
http://dx.doi.org/10.1016/j.bbadis.2013.05.027
Please cite this article as: J. Sanchez-Gurmac
http://dx.doi.org/10.1016/j.bbadis.2013.05.0
more favorablemetabolic
s also present as fat distri-
trunk cavity) or subcutaneous (below the skin). There is not a uni-
formly applied system for describing the anatomical location of each
and not all fat is equalwith somedepots having
properties than others [1]. Some lipodystrophie
1. Introduction:
Obesity is a risk factor formanydisea
diovascular disease, and cancer. Obesity
ceeds energy expenditure causing adipo
body fat distribution patterns are high
why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex
because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies
further suggest that the vasculature may provide a niche supporting both brown and white adipocyte pro-
genitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between
adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning par-
ticularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting
lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body
fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled:
Modulation of Adipose Tissue in Health and Disease.
© 2013 Elsevier B.V. All rights reserved.
uding type2diabetes, car-
when energy intake ex-
e to overgrow. However,
able between individuals
tissue (BAT). WAT (the primary site of energy storage) is mostly com-
posed of adipocytes containing a large unilocular lipid droplet. WATs
are found throughout the body; however, the distribution of mass
between each depot varies in the population as a function of
genetics, age, and for some depots, sensitivity to hormones and gluco-
corticoids. WAT location is often classified as being visceral (in the
Brite or beige adipocyte
Myf5
w
hite adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to
White adipose tissue (WAT)
Brown adipose tissue (BAT) brown adipocytes originate
Adipocyte lineages: Tracing back the orig
Joan Sanchez-Gurmaches, David A. Guertin ⁎
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, M
a b s t r a c ta r t i c l e i n f o
Article history:
Received 11 February 2013
Received in revised form 22 May 2013
Accepted 24 May 2013
Available online xxxx
Keywords:
The obesity epidemic has in
opment. Adipose tissue is ge
or brown adipose tissue (B
adipocytes (brown in whit
exist in adult humans sugg
combat obesity. To understa
adipocytes back to their adu
Review
j ourna l homepage: www.
morphological appear-
AT) or brown adipose
ion of Adipose Tissue in Health
Guertin).
rights reserved.
hes, D.A. Guertin, Adipocyte li
27
s of fat☆
605, USA
sified efforts to understand the mechanisms controlling adipose tissue devel-
ally classified as white adipose tissue (WAT), the major energy storing tissue,
, which mediates non-shivering thermogenesis. It is hypothesized that brite
ay represent a third adipocyte class. The recent realization that brown fat
increasing brown fat energy expenditure could be a therapeutic strategy to
adipose tissue development, several groups are tracing the origins of mature
recursor and embryonic ancestors. From these studies emerged a model that
ophysica Acta
evie r .com/ locate /bbad is
and mesenteric WAT (mWAT; lining the surface of the intestines)
(Fig. 1). Although the primary function of WAT is energy storage, it
also functions as an endocrine organ secreting hormones and cyto-
kines such as leptin and adiponectin that regulate feeding and metab-
olism [5]. Epidemiological studies have found that the accumulation of
visceral fat (determined by high waist-to-hip ratio) associates with
metabolic disease (i.e. insulin resistance, type 2 diabetes, dyslipidemia,
neages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013),
2 J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx
hypertension, atherosclerosis, hepatic steatosis, and cancer) while the
accumulation of subcutaneous WAT associates with improved insulin
sensitivity and low risk for developing type 2 diabetes [6–14].
Brown adipocytes contain multiple smaller (multilocular) lipid
droplets, are rich in mitochondria, and reside in depots that are highly
innervated and vascularized. In rodents, BAT is located in discrete
depots in interscapular (iBAT), sub-scapular (sBAT), and cervical (cBAT)
Fig. 1. The Myf5 lineage contribution to the precursor pool in each fat depot varies with
its anatomical location. The contribution of the Myf5 lineage to the adipocyte precursor
cell compartment (defined as CD31−CD45−Terr119−CD29+CD34+Sca1+ cells) was
recently determined by lineage tracing with Myf5-Cre;R26R-YFP mice. More than 95%
of the precursors in brown fat are labeled with Myf5-Cre. In the anterior subcutaneous
WATs (including interscapular and axial WATs) nearly 50% of the precursors trace to
Myf5+ precursors, and in the rWAT (a visceral WAT), the Myf5 precursors give rise to
approximately 70% of the adipocyte precursor cell pool. In contrast, the Myf5 lineage
contributes very little to the adipocyte precursor pool in ingWAT and pgWAT, which are
90–95% Myf5neg. The contribution of the Myf5 lineage to the intramuscular adipogenic
precursor pool (defined with slightly different cell surface markers) is very low. Dotted
line indicates the abdominal cavity. References provided in the text.
regions of the upper anterior side of the trunk and neck (Fig. 1) [4]. BAT
also grows around parts of the aorta and kidneys [15]. These depots
are often called “classical” BAT to distinguish them from brown-
adipocyte-like cells, called brite adipocytes, which reside within some
WATs (discussed below). In contrast to energy storing white adipocytes,
brown adipocytes are specialized to expend energy to generate heat in a
process called adaptive thermogenesis [16]. BAT is stimulated by the
sympathetic nervous system following exposure to cold temperature
and regulates the acute non-shivering thermogenesis response as well
as the adaptive cold acclimatization response following chronic cold
exposure. Thermogenesis is meditated by uncoupling protein 1 (UCP1),
which embeds in the inner mitochondrial membrane, and produces
heat by dissipating the proton electrochemical gradient over the inter-
mitochondrial membrane space without generating ATP [17]. BAT stores
energy for thermogenesis as perilipin coated lipid droplets and glycogen
granules [18,19] and upon stimulation rapidly increases glucose and
FA uptake to replenish its supplies. The high glucose uptake capacity of
BATmakes it readily detectable by 18F-fluorodeoxyglucose positron emis-
sion tomography (FDG–PET) [17,20,21]. While long thought to be critical
only in rodents and newborn humans, the recent realization that BAT
functions in adult humans (made possible by its sensitivity to FDG–PET)
[22–26] raises the possibility that therapeutically controlling BAT growth
and/or energy expenditure could be a strategy to combat obesity [27–34].
Interest is also growing in a third potential class of adipocyte called
a brite adipocyte (also known as a “beige”, “inducible brown”, or
“recruitable brown” adipocyte) [19,21,35–41]. This mysterious type of
adipocyte exists among classical white adipocytes and is morphologi-
cally indistinguishable from its neighboring white adipocytes in the
basal or unstimulated state. However, upon stimulation by chronic
cold exposure (or other mechanisms that mimic beta-adrenergic
Please cite this article as: J. Sanchez-Gurmaches, D.A. Guertin, Adipocyte li
http://dx.doi.org/10.1016/j.bbadis.2013.05.027
stimulation) they become multilocular and begin expressing UCP1
[19,21,40,42]. The presence of brite adipocytes in the WAT of mice is
not homogeneous. For example, many adipocytes in ingWAT or rWAT
becomemultilocular and induce UCP1 following stimulation; however,
only a few UCP1+ brite adipocytes arise in pgWAT in the same mice
[19,40]. Brite adipocyte content varies between mouse strains and cor-
relates with overall strain sensitivity to high fat diet [43–47]. Whether
brite adipocytes form by trans-differentiation of existing white adipo-
cytes or arise from a unique preadipocyte lineage is under debate
(discussed below) [19,40,41,48–51]. Perhaps the biggest unresolved
issue pertaining to brite adipocytes is whether these cells actually con-
tribute significantly to thermogenesis. For example, while UCP1mRNA
is induced in brite adipocytes several hundred-fold relative to white
adipocytes (which barely expresses UCP1) [38,52,53], the total UCP1
expression is still an order of magnitude lower than that detected in
brown adipose tissue [52]. In fact, the maximum thermogenic capacity
of brite fat has been estimated at only ~10% of classical brown fat in
mice. A debate is underway as to whether human brown fat is more
similar to brite fat or to classical brown fat in mice. Early reports argue
that what is currently being called human brown fat is more similar to
murine brite fat than to classical murine brown fat [48,49]. However,
recent studies that more extensively profile different layers of adipose
tissue in newborns and adults reveals that humans have brown fat
deposits—particularly in the neck—that have a classic brown fat signa-
ture [54,55]. Interestingly, there appears to be a gradient of fat cell
types in the neck, with deep neck fat being classical BAT, intermediate
cells possibly beingmore brite-like, and themost peripheral adipocytes
being classical white adipocytes [55]. These findings are important
considering the growing emphasis on developing therapeutic strategies
to induce the “browning” of WAT in humans [35,56–59] because they
suggest that the studies of classical brown fat in mice could also have
important therapeutic implications in humans. The physiological signif-
icance and regulatory mechanisms of brown versus brite fat in humans
clearly need to be determined.
Each individual fat depot is complex, composed not only of mature
adipocytes but also of adipocyte precursor cells, fibroblasts, nerves,
vascular cells, macrophages, and other cell types (collectively called
the stromal vascular fraction or SVF). Adding to their complexity is
the fact that adipose tissues are functionally heterogeneous. Although
the sharpest functional divergence is clearly between energy storing
WAT and energy-expending BAT, functional divergence is also evi-
dent between WATs best exemplified by the risk associated with
excess visceral fat versus subcutaneous fat. However, such simple
distinctions are oversimplifications because differences in lipogenic
activity, cell dynamics, proliferative and differentiation capacity, and
gene expression even between categorically similar WAT depots
have been reported [60–67]. Heterogeneity likely exists even within
a single WAT as suggested by studies showing that neighboring
adipocytes can respond differently to genetic perturbations or drugs
[68–72]. The existence of such heterogeneity within and between fat
tissues suggests broad conclusions should not be based on a limited
survey of select fat depots, and that each depot should be considered
separately.
Does adipocyte tissue heterogeneity reflect different developmen-
tal origins of adipocytes, variances in the developmental cues a partic-
ular adipocyte may experience during differentiation, or extracellular
influences on the mature adipocytes unique to the local cell or tissue
environment? Answering these questions could lead to new anti-
obesity therapies, improve the understanding of lipodystrophies, and
increase the prospect of using adipocyte progenitor cells for cell-based
therapeutics [17,73,74].
3. The origin of adipocytes
Central to understanding the complexities and heterogeneity
of adipose tissue is to understand where the path to becoming an
neages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013),
Table 1
Summary of recent lineage tracing studies of pre- and mature adipocytes.
Genetic approach Promoter
location
Rationale Reported result References
White adipocytes sox10-Cre;R26R-eYFP Transgene Sox10 expresses in pre- and migratory neural
crest cells at all rostro-caudal levels
Mature adipocytes in the salivary gland labeled
positive; pgWAT and ingWAT labeled negative
[103,139]
PPARγ-tTA;TRE-Cre;
R26R-LacZ
Knock-in PPARγ is a nuclear receptor expressed in all
tissues and is critical for adipogenesis
ingWAT and rWAT positive; some positive SVF
cells
[82]
aP2-GFP Transgene aP2 (FABP4) expresses in mature adipocytes
and is a target of PPARγ
ingWAT positive [82]
aP2-Cre;R26R-LacZ Transgene Described above ingWAT and pgWAT positive [82]
PDGFRβ-Cre;
R26R-LacZ
Transgene PDFGRβ is expressed in vascular mural cells ingWAT and rWAT positive [82,140]
myf5-Cre;R26R-eYFP Knock-in Myf5 is a muscle differentiation transcription
factor that is first expressed in the
dermomyotome at E8.0 and expresses in adult
satellite cells
ingWAT and pgWAT negative [116,117]
wnt1-Cre;R26R-eYFP Transgene Restrictive marker of migrating neural crest
cells
Cephalic WAT positive; pgWAT and ingWAT
negative. 70% of adipocyte precursors in cephalic
WAT positive; all ingWAT adipocyte precursors
negative
[104,141]
LysM-Cre;R26R-LacZ Knock-in The lysozyme M is exclusively expressed in
macrophages and granulocytes
5–20% of pgWAT adipocytes positive [110,111]
VE-cadherin-Cre;
R26R-LacZ
Knock-in VE-cadherin is expressed in endothelial cells, is
involved in cell adhesion, and is essential for
vascular system development
ingWAT and pgWAT positive [96,98]
VE-cadherin-Cre;
R26R-eGFP
Knock-in Described above Subset of mature adipocytes in the pgWAT
positive
[96,98]
VE-cadherin-CreERT2;
R26R-LacZ
Knock-in VE-cadherin-CreERT2 is a tamoxifen-inducible
version of the VE-cadherin-Cre
Numerous adipocytes in the ingWAT, pgWAT
and BAT positive
[97,98]
ZFP423-GFP Knock-in Zfp423 is a transcriptional regulator broadly
expressed but essential for preadipocyte
commitment
ingWAT positive [95]
pax3-Cre;
R26R-mTmG
Knock-in Pax3 is a muscle differentiation transcription
factor first expressed in dorsal neural crest and
somites; it cooperates with Myf5 to drive
muscle development
50% of the adipogenic SVF cells from asWAT
positive
[123,124]
myf5-Cre;R26R-LacZ Knock-in Described above Mature adipocytes from asWAT and rWAT
positive; few mature adipocytes from ingWAT
and pgWAT positive; 50–60% of adipogenic SVF
cells from asWAT and rWAT positive; b2% from
the ingWAT and pgWAT positive
[83,117]
myf5-Cre;R26R-eYFP Knock-in Described above 50–70% of the adipocyte precursors from asWAT
and rWAT positive; b10% of the adipocyte
precursors from pgWAT and ingWAT positive
[83,117]
vav1-Cre;
R26R-mTmG
Knock-in Vav1 is a proto-oncogene that expresses in the
hematopoietic and lymphoid systems
All adipocyte precursors and mature adipocytes
from ingWAT, pgWAT, rWAT andmWATnegative
[100,112]
tie2-Cre;R26R-mTmG Transgene Tie2 is an angiopoietin receptor specific to
endothelial cells and some hematopoietic cells
All adipocyte precursors and mature adipocytes
from ingWAT, pgWAT, rWAT andmWATnegative
[100,142]
VE-cadherin-Cre;
R26R-mTmG
Knock-in Described above All adipocyte precursors and mature adipocytes
from ingWAT, pgWAT, rWAT andmWATnegative
[96,100]
PDFGRα-Cre;
R26R-mTmG
Transgene PDGFRα is expressed in most mesenchymal
cells can activate the MAPK, PI3K and PLCγ
signaling pathways
All adipocyte precursors and mature adipocytes
from ingWAT, pgWAT, rWAT and mWAT
positive
[100,143]
Brown adipocytes En1-Cre;R26R-LacZ Knock-in Engrailed 1 is a homeobox transcription factor
that expresses in cells of the central
dermomyotome
BAT positive [114,144]
myf5-Cre;R26R-eYFP Knock-in Described above BAT positive [116,117]
pax7-CreERT2;
R26R-LacZ
Knock-in Pax7 is expressed in medial and central cells of
the dermomyotome and in adult satellite cells
BAT positive [121,122]
myf5-Cre;R26R-LacZ Knock-in Described above BAT positive; >99% of adipogenic BAT SVF cells
positive
[83,117]
myf5-Cre;R26R-eYFP Knock-in Described above >95% of BAT adipocyte precursors positive [83,117]
VE-cadherin-Cre;
R26R-LacZ
Knock-in Described above BAT positive [96,98]
VE-cadherin-CreERT2;
R26R-LacZ
Knock-in Described above Many brown adipocytes positive [97,98]
Brite adipocytes myf5-Cre;R26R-eYFP Knock-in Described above Brite adipocytes in ingWAT negative [116,117]
myf5-Cre;R26R-LacZ Knock-in Described above CL316,243 induced brite adipocytes in asWAT
and rWAT positive; brite adipocytes induced in
ingWAT negative
[83,117]
VE-cadherin-CreERT2;
R26R-LacZ
Knock-in Described above Rosiglitazone induced bright adipocytes in
ingWAT positive
[97,98]
UCP1-CreERT2;
R26R-tdRFP
Knock-in UCP1 is the most accepted functional marker of
brown adipocytes
Brite and white adipocytes interconvert in
ingWAT depending on the temperature
[51]
(continued on next page)
3J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx
Please cite this article as: J. Sanchez-Gurmaches, D.A. Guertin, Adipocyte lineages: Tracing back the origins of fat, Biochim. Biophys. Acta (2013),
http://dx.doi.org/10.1016/j.bbadis.2013.05.027
4 J. Sanchez-Gurmaches, D.A. Guertin / Biochimica et Biophysica Acta xxx (2013) xxx–xxx
adipocyte begins. Moreover, strategies targeting nascent adipocytes
could be useful in fighting obesity; however the identity of the adipo-
cyte progenitor cells is just beginning to be unraveled. As obesity
progresses, adipose tissues grow by hypertrophy (increasing the size
of their adipocytes) and by hyperplasia (increasing the number of
adipocytes) [75–79]. A yearly adipocyte turnover rate for lean and
obese humans of 10% has been reported [79], but because mature
adipocytes do not divide, a resident adipocyte precursor cell must exist.
Undifferentiated adipocyte progenitor cells were long assumed
to
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