The main parenchymal cells of the adipose organ are adipocytes. White adipocytes store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions can both originate from endothelial cells, and co-exist in the multiple fat depots of the adipose organ – a feature that I propose is crucial for this organ’s plasticity. This poster review provides an overview of the adipose organ, describing its anatomy, cytology, physiological function and histopathology in obesity. It also highlights the remarkable plasticity of the adipose organ, explaining theories of adipocyte transdifferentiation during chronic cold exposure, physical exercise or lactation, as well as in obesity. White-to-brown adipocyte transdifferentiation is of particular medical relevance, because animal data indicate that higher amounts of brown adipose tissue are positively associated with resistance to obesity and its co-morbidities, and that ‘browning’ of the adipose organ curbs these disorders.

Introduction

Adipose tissues are generally regarded as connective tissues without a specific anatomy. However, accumulating data support the idea that adipose tissues are organized to form a large organ with discrete anatomy, specific vascular and nerve supplies, complex cytology, and high physiological plasticity (Cinti, 1999; Cinti, 2011). The organ is made up of several depots located in two compartments of the body: some are below the skin (subcutaneous depots) and some are in the trunk (visceral depots). Adipose tissues can thus be considered a multi-depot organ (Cinti, 2001; Cinti, 2005). This organ contributes to many of an organism’s crucial survival needs: thermogenesis, lactation, immune responses and fuel for metabolism. In this article and the accompanying poster, I provide a brief overview of the adipose organ in mice and humans, touching on cytology, physiological function and dynamics during health and disease. Because most of the data available derive from mouse studies, the poster illustrates the adipose organ of mice; however, many of the anatomical, physiological and pathological aspects are common to the adipose organ of humans. The anatomy of female mice is shown to emphasize changes in the adipose organ that occur during pregnancy and lactation.

Cytology

The main parenchymal cells of the adipose organ are called adipocytes. There are two main types of adipocytes, which are easy to distinguish by morphology: white adipocytes [see top scanning electron microscopy (SEM) image in blue panel of poster] are leptin- and S100-B-immunoreactive spherical cells with ∼90% of their volume comprising a single cytoplasmic lipid droplet and a ‘squeezed’ nucleus, whereas brown adipocytes (see bottom SEM image in blue panel of poster) are polygonal cells with a roundish nucleus and several cytoplasmic lipid droplets. Brown adipocytes are also characterized by numerous large mitochondria packed with cristae. Mitochondria in brown adipocytes are marked by the expression of uncoupling protein 1 (UCP1), a unique protein that uncouples oxidative phosphorylation from ATP synthesis and thereby results in the production of heat (thermogenesis) (Cannon and Nedergaard, 2004; Ricquier, 2005; Frontini et al., 2007). Thus, white and brown adipocytes are quite different in their morphology and physiology: white adipocytes store energy for the metabolic needs of the organism, whereas brown adipocytes burn energy for thermogenesis. Both cell types are contained in the multiple depots of the adipose organ (Murano et al., 2005; Murano et al., 2009; Vitali et al., 2012). White adipocytes of different sizes are present in subcutaneous depots (mainly large adipocytes) and visceral depots (mainly small adipocytes) (Murano et al., 2008; Barbatelli et al., 2010). Brown adipocytes in visceral depots are mainly found near the aorta. Paucilocular adipocytes, which are cells with intermediate morphology between that of white and brown adipocytes, are also present in the adipose organ. It should be noted that some groups also refer to ‘beige’ (Ishibashi and Seale, 2010) or ‘brite’ (brown in white) (Petrovic et al., 2010; Waldén et al., 2012) regions of white adipose tissue, containing brown or brown-like adipocytes.

Anatomy

In mice, the adipose organ is made up of two subcutaneous depots and several visceral depots. The anterior subcutaneous depot is quite complex (Frontini and Cinti, 2010; Vitali et al., 2012). Its main volume is located in the upper dorsal area at the level of the scapulae. Several parts of it have been described in literature as distinct depots: interscapular, subscapular, axillary and cervical. The posterior subcutaneous depot is located mainly in the lower ventral part of the body, and is formed of three parts (also often described as distinct depots): dorso-lumbar, inguinal and gluteal. One or two lymph nodes are present in the dorso-lumbar and inguinal parts. The truncal depots are contained in the mediastinum and abdomen. All truncal depots are closely associated with the aorta and its main collaterals. In females, perirenal, periovarian, parametrial and perivesical fat form a single anatomical structure called the abdominopelvic depot (Murano et al., 2005; Frontini and Cinti, 2010; Vitali et al., 2012). Furthermore, subcutaneous depots in female mice are infiltrated by ramified epithelial ducts ending in five symmetrical pairs of nipples; thus, in female mice, all of the subcutaneous tissue can be considered as part of ten mammary glands (see Cinti, 1999; Masso-Welch et al., 2000).

The composition of the adipose organ varies in different anatomical locations, and under different conditions, as represented by different colors in the blue panel of the poster. In normal animals in a warm environment, regions close to the aorta and its main collaterals are shown in brown, representing brown adipose tissue (BAT). Note that brown adipocytes are normal components of several subcutaneous and visceral depots and are not exclusive to interscapular fat. BAT is mainly formed of UCP1-expressing brown adipocytes, a rich capillary network and a high density of noradrenergic parenchymal fibers (shown as blue lines in the poster). The majority of the adipose organ is shown in yellow in the poster, representing white adipose tissue (WAT), which is mainly formed of leptin- and S100-B-expressing white adipocytes (Cinti et al., 1989; Barbatelli et al., 1993; Cinti et al., 1997) and a network that is five- to six-times less vascularized and innervated then BAT (Nechad, 1986). The areas shown in peach are mainly composed of paucilocular cells that can be positive for UCP1 and S100-B, depending on their differentiation stage (Barbatelli et al., 1993). On the basis of electron microscopy, paucilocular cells show features that are intermediate between white and brown adipocytes, including mitochondrial pleomorphism (Barbatelli et al., 2010), as illustrated in the green panel of the poster.

Pericardic, omental (which are very small in mice and not represented in the poster), mesenteric and subcutaneous depots are characterized by the presence of lymphatic tissue (Cinti, 2011). Moreover, mesenteric, omental and pericardic fat contain lymphocytes that are in close contact with adipocytes. Of note, lymphocytes express the leptin receptor, and visceral fat lymphocytes have been discovered to have specific functional properties (Fantuzzi and Faggioni, 2000; Moro et al., 2010). Furthermore, there are one or two lymph nodes in the posterior subcutaneous depots as well as in other anatomical sites such as the popliteal fat depots (Almind et al., 2007). Thus, it is reasonable to assume a functional relationship between adipocytes and lymphocytes, and this could be altered in obesity.

Dynamics of adipose organ composition

Innervation and adaptation to temperature changes

The adipose organ is innervated (Bartness and Bamshad, 1998; Giordano et al., 2008; Bartness et al., 2010), enabling it to interface with the nervous system and respond to physiological and environmental cues. Nerve endings in adipose tissue reach the vasculature and adipocytes (Cannon et al., 1986). Most of the parenchymal fibers (i.e. nerve fibers in contact with adipocytes) express tyrosine hydroxylase (TH), an enzyme that is widely considered to be a marker of noradrenergic fibers (Giordano et al., 2008). Thermogenesis is required when animals are exposed to temperatures below thermoneutrality and implies sympathetic nervous system activation (Himms-Hagen, 1986). Norepinephrine acts on beta3 adrenoreceptors, which promote the molecular pathway for thermogenesis in brown adipocytes (Cannon and Nedergaard, 2004). Our own data show that the density of TH-expressing parenchymal fibers is much higher in the brown parts of the adipose organ than in white parts and, during cold exposure, the density of these fibers increases in parallel with the increase in number of brown adipocytes (Murano et al., 2009; Vitali et al., 2012). Thus, the adipose organ of cold-exposed mice is browner and more densely innervated than the adipose organ of mice in a warm environment, as shown in the blue panel of the poster.

The adipose organ of humans behaves similarly to the adipose organ of mice. Metabolically active BAT is detectable by positron emission tomography (PET) (Nedergaard et al., 2007; Cypess et al., 2009; Saito et al., 2009; van Marken Lichtenbelt et al., 2009; Virtanen et al., 2009). Similarly to mouse BAT, human BAT is composed of UCP1-expressing adipocytes that are densely innervated by TH-immunoreactive fibers (Zingaretti et al., 2009). Interestingly, cold-exposed normal subjects and patients suffering from pheochromocytoma (a norepinephrine-secreting tumor of the adrenal gland) show increased BAT by PET with an anatomic distribution similar to that of mice – that is, closely associated with the aorta and its main collaterals (Kuji et al., 2008; Saito et al., 2009).

Adipose organ plasticity

The origin of newly formed brown adipocytes in the adipose organ of cold-exposed animals – a phenomenon referred to as ‘browning’ – is under debate (Timmons et al., 2007; Seale et al., 2008; Barbatelli et al., 2010). Notably, data obtained from three independent groups using different experimental approaches support the idea that brown-like adipocytes arising in predominantly white fat depots in response to cold exposure are ontogenically different from those in the classic interscapular BAT (Atit et al., 2006; Seale et al., 2008; Petrovic et al., 2010).

Our own data support the idea that most of the brown adipocytes responsible for the browning phenomenon observed after adrenergic stimulus or cold exposure (with the exception of the interscapular fat) derive from a direct transformation of white adipocytes into brown adipocytes (white-to-brown transdifferentiation) (Himms-Hagen et al., 2000; Barbatelli et al., 2010). The recent discovery that both brown and white adipocytes derive from vascular endothelial cells of the adipose organ brings strong new support to the transdifferentiation theory (Tran et al., 2012; Gupta et al., 2012). However, it should be noted that other routes of adipocyte differentiation have been proposed (Crossno et al., 2006; Maumus et al., 2011; Lee et al., 2012). The transdifferentiation theory explains why these two different cell types are contained together in the same organ: in special cases (such as chronic cold exposure) the white part of the organ might ‘help’ the brown part by forming new BAT (Cinti, 2009a). The many reasons supporting our theory of transdifferentiation are discussed in more detail elsewhere (Cinti, 2009a; Cinti, 2009b; Cinti, 2011). Notably, WAT also expresses beta3 adrenoceptors (De Matteis et al., 2002), and the browning phenomenon is blunted in beta3 adrenoceptor knockout mice (Jimenez et al., 2003; Barbatelli et al., 2010). In addition, a wide variety of other mechanisms have been reported to be involved in BAT activation and browning of the adipose organ (see Box 1).

The potential to manipulate the inherent plasticity of the adipose organ is important because it is widely accepted that animals with more BAT are more resistant to obesity and type 2 diabetes (T2D) (Kopecky et al., 1996; Collins et al., 1997; Guerra et al., 1998; Almind et al., 2007; Vitali et al., 2012). Conversely, animals without functional BAT are prone to obesity and T2D (Lowell et al., 1993; Bachman et al., 2002; Feldmann et al., 2009). Furthermore, obesity in rats is curbed when they are treated with beta3 adrenoceptor agonists, which induce the browning phenomenon in WAT (Ghorbani et al., 1997; Ghorbani and Himms-Hagen, 1997). These data also seem to be valid for humans (Oberkofler et al., 1997; Cypess and Kahn, 2010).

Box 1.
Mechanisms reportedly involved in BAT activation and browning of the adipose organ

Very recently, a newly identified hormone named irisin, which is produced by skeletal muscle during physical exercise, has been shown to induce browning of WAT in mice (Boström et al., 2012). Administration of irisin to mice with diet-induced obesity and insulin resistance reduced these conditions. This hormone is also produced in humans, suggesting that it could be manipulated to modulate plasticity of the adipose organ. Thus, both physiological stimuli (such as cold or physical exercise) or pharmaceutical derivates could be used for the treatment of obesity and related disorders.

Lactation: a special case for adipose organ plasticity

During pregnancy and lactation, all subcutaneous depots of female mice transform into milk-secreting glands. This hormone-regulated phenomenon suggests that there is a progressive reduction in the number of adipocytes in parallel with an increase in the number of epithelial cells that form the functional adenomeres of the mammary glands (shown as green lines in the blue panel of the poster). Data from our laboratory support the idea that these newly formed epithelial cells derive from a direct transformation of adipocytes into milk-secreting epithelial cells (adipo-epithelial transdifferentiation). The process seems to be reversible and the epithelial cells, which are marked by the expression of whey acidic protein (WAP; a milk protein expressed only in milk-secreting epithelial cells in mammary glands), revert into adipocytes in the post-lactation period (Morroni et al., 2004; De Matteis et al., 2009).

Pathology

When the energy balance is positive (i.e. when food intake is greater than energy expenditure), the white part of the adipose organ expands. This expansion occurs via an increase in the volume of existing adipocytes as well as the formation of new white adipocytes (Hausman et al., 2001). These newly formed white adipocytes develop from pre-adipocytes, but also from a direct transformation of brown into white adipocytes (Cinti et al., 1997; Bachman et al., 2002). It was recently discovered that knockdown of SMAD3 (a component of the TGFβ signaling pathway) in mice induces browning of the adipose organ and protects from diabetes and obesity (Yadav et al., 2011), suggesting that TGFβ could be involved in transdifferentiation. Notably, levels of TGFβ are also correlated with body mass index. This completes the hypothesis of adipose organ plasticity: energy accumulation induces BAT to ‘help’ WAT store more energy (i.e. induces brown-to-white adipocyte transdifferentiation).

Storing of excess energy over time can lead to obesity and associated conditions, such as insulin resistance. These conditions are associated with adipose tissue pathology, to which many different factors probably contribute. In particular, macrophages seem to contribute to insulin resistance and other conditions associated with obesity. The obese adipose organ is infiltrated by macrophages, and macrophage infiltration of fat is coincident with the appearance of insulin resistance (Weisberg et al., 2003; Xu et al., 2003; Strissel et al., 2007). The number of macrophages is much higher in visceral than in subcutaneous fat, both in diet-induced and genetic obesity (Strissel et al., 2007; Murano et al., 2008). Macrophages [>90% of which are immunoreactive for galactose-specific lectin 3 (also known as MAC2)] form crown-like structures (CLSs) surrounding dead adipocytes, which are phagocytosed by the macrophages (see bottom-right panel of the poster) (Cinti et al., 2005). Tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1α (IL-1α) and other pro-inflammatory cytokines are produced by macrophages, and the ability of such cytokines to interfere with the physiology of insulin receptor signaling is well known (Gregor and Hotamisligil, 2011). CLSs are also present in the fat of obese humans (Cinti et al., 2005). Macrophage infiltration is positively correlated with the size of adipocytes both in visceral and subcutaneous fat, but can occur independently of obesity per se, because lean mice deficient for hormone-sensitive lipase have hypertrophic adipocytes and the same amount of CLSs as obese mice (Cinti et al., 2005). Notably, obese mice and humans without adipocyte hypertrophy (hyperplastic obesity) do not show CLSs in fat and are insulin sensitive (Cinti et al., 2005; Hoffstedt et al., 2010). Visceral adipocytes in obese mice are smaller than subcutaneous adipocytes, but visceral fat has a higher amount of CLSs, suggesting a different ‘critical death size’ (CDS) for adipocytes in visceral fat (Murano et al., 2008; Virtue and Vidal-Puig, 2010). Thus, visceral adipocytes die at a smaller CDS, which might explain the well-known dangerous metabolic consequences of visceral fat accumulation (Cinti, 2009a).

On the basis of the current data, the sequence of events linking obesity with insulin resistance could be:

  • adipocyte hypertrophy due to obesity;

  • adipocyte stress, possibly involving hypoxia (Wood et al., 2009) and the production of chemoattractants;

  • chemoattraction and infiltration of macrophages;

  • death of adipocytes on reaching the CDS (visceral adipocytes die first);

  • chronic reabsorption of adipocyte remnants by macrophages, accompanied by a massive production of cytokines by macrophages;

  • increased levels of circulating cytokines contributes to insulin resistance in peripheral tissues.

Conclusion

In conclusion, the adipose organ is a complex structure with highly plastic properties that include the ability of its parenchymal cells (the adipocytes) to reprogram their genes and transdifferentiate into cells with a different morphology and physiology (a state that is physiologically reversible). It is hoped that this plasticity of the adipose organ can be exploited in the next generation of therapeutic strategies to combat the increasing incidence of metabolic diseases, including obesity and T2D.

This article is part of a special issue on obesity: see related articles in Vol. 5, issue 5 of Dis. Model. Mech. at http://dmm.biologists.org/content/5/5.toc.

FUNDING

With support of Grant DIABAT European Community’s FP7, Grant agreement number HEALTH-F2-2011-278373.

REFERENCES

Almind
K.
,
Manieri
M.
,
Sivitz
W. I.
,
Cinti
S.
,
Kahn
C. R.
(
2007
).
Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice
.
Proc. Natl. Acad. Sci. USA
104
,
2366
2371
.
Atit
R.
,
Sgaier
S. K.
,
Mohamed
O. A.
,
Taketo
M. M.
,
Dufort
D.
,
Joyner
A. L.
,
Niswander
L.
,
Conlon
R. A.
(
2006
).
Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse
.
Dev. Biol.
296
,
164
176
.
Bachman
E. S.
,
Dhillon
H.
,
Zhang
C. Y.
,
Cinti
S.
,
Bianco
A. C.
,
Kobilka
B. K.
,
Lowell
B. B.
(
2002
).
betaAR signaling required for diet-induced thermogenesis and obesity resistance
.
Science
297
,
843
845
.
Barbatelli
G.
,
Morroni
M.
,
Vinesi
P.
,
Cinti
S.
,
Michetti
F.
(
1993
).
S-100 protein in rat brown adipose tissue under different functional conditions: a morphological, immunocytochemical, and immunochemical study
.
Exp. Cell Res.
208
,
226
231
.
Barbatelli
G.
,
Murano
I.
,
Madsen
L.
,
Hao
Q.
,
Jimenez
M.
,
Kristiansen
K.
,
Giacobino
J. P.
,
De Matteis
R.
,
Cinti
S.
(
2010
).
The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation
.
Am. J. Physiol. Endocrinol. Metab.
298
,
E1244
E1253
.
Bartness
T. J.
,
Bamshad
M.
(
1998
).
Innervation of mammalian white adipose tissue: implications for the regulation of total body fat
.
Am. J. Physiol.
275
,
R1399
R1411
.
Bartness
T. J.
,
Vaughan
C. H.
,
Song
C. K.
(
2010
).
Sympathetic and sensory innervation of brown adipose tissue
.
Int. J. Obes.
34
,
S36
S42
.
Boström
P.
,
Wu
J.
,
Jedrychowski
M. P.
,
Korde
A.
,
Ye
L.
,
Lo
J. C.
,
Rasbach
K. A.
,
Boström
E. A.
,
Choi
J. H.
,
Long
J. Z.
, et al. 
(
2012
).
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
.
Nature
481
,
463
468
.
Cannon
B.
,
Nedergaard
J.
(
2004
).
Brown adipose tissue: function and physiological significance
.
Physiol. Rev.
84
,
277
359
.
Cannon
B.
,
Nedergaard
J.
,
Lundberg
J. M.
,
Hökfelt
T.
,
Terenius
L.
,
Goldstein
M.
(
1986
).
‘Neuropeptide tyrosine’ (NPY) is co-stored with noradrenaline in vascular but not in parenchymal sympathetic nerves of brown adipose tissue
.
Exp. Cell Res.
164
,
546
550
.
Cederberg
A.
,
Grønning
L. M.
,
Ahrén
B.
,
Taskén
K.
,
Carlsson
P.
,
Enerbäck
S.
(
2001
).
FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance
.
Cell
106
,
563
573
.
Cinti
S.
(
1999
).
The Adipose Organ
.
Milan, Italy
:
Kurtis
.
Cinti
S.
(
2001
).
The adipose organ: morphological perspectives of adipose tissues
.
Proc. Nutr. Soc.
60
,
319
328
.
Cinti
S.
(
2005
).
The adipose organ
.
Prostaglandins Leukot. Essent. Fatty Acids
73
,
9
15
.
Cinti
S.
(
2009a
).
Reversible physiological transdifferentiation in the adipose organ
.
Proc. Nutr. Soc.
68
,
340
349
.
Cinti
S.
(
2009b
).
Transdifferentiation properties of adipocytes in the adipose organ
.
Am. J. Physiol. Endocrinol. Metab.
297
,
E977
E986
.
Cinti
S.
(
2011
).
Between brown and white: novel aspects of adipocyte differentiation
.
Ann. Med.
43
,
104
115
.
Cinti
S.
,
Cigolini
M.
,
Morroni
M.
,
Zingaretti
M. C.
(
1989
).
S-100 protein in white preadipocytes: an immunoelectronmicroscopic study
.
Anat. Rec.
224
,
466
472
.
Cinti
S.
,
Frederich
R. C.
,
Zingaretti
M. C.
,
De Matteis
R.
,
Flier
J. S.
,
Lowell
B. B.
(
1997
).
Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue
.
Endocrinology
138
,
797
804
.
Cinti
S.
,
Mitchell
G.
,
Barbatelli
G.
,
Murano
I.
,
Ceresi
E.
,
Faloia
E.
,
Wang
S.
,
Fortier
M.
,
Greenberg
A. S.
,
Obin
M. S.
(
2005
).
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans
.
J. Lipid Res.
46
,
2347
2355
.
Collins
S.
,
Daniel
K. W.
,
Petro
A. E.
,
Surwit
R. S.
(
1997
).
Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice
.
Endocrinology
138
,
405
413
.
Crossno
J. T.
 Jr
,
Majka
S. M.
,
Grazia
T.
,
Gill
R. G.
,
Klemm
D. J.
(
2006
).
Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells
.
J. Clin. Invest.
116
,
3220
3228
.
Cummings
D. E.
,
Brandon
E. P.
,
Planas
J. V.
,
Motamed
K.
,
Idzerda
R. L.
,
McKnight
G. S.
(
1996
).
Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A
.
Nature
382
,
622
626
.
Cypess
A. M.
,
Kahn
C. R.
(
2010
).
Brown fat as a therapy for obesity and diabetes
.
Curr. Opin. Endocrinol. Diabetes Obes.
17
,
143
149
.
Cypess
A. M.
,
Lehman
S.
,
Williams
G.
,
Tal
I.
,
Rodman
D.
,
Goldfine
A. B.
,
Kuo
F. C.
,
Palmer
E. L.
,
Tseng
Y. H.
,
Doria
A.
, et al. 
(
2009
).
Identification and importance of brown adipose tissue in adult humans
.
N. Engl. J. Med.
360
,
1509
1517
.
De Matteis
R.
,
Arch
J. R.
,
Petroni
M. L.
,
Ferrari
D.
,
Cinti
S.
,
Stock
M. J.
(
2002
).
Immunohistochemical identification of the beta(3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine
.
Int. J. Obes. Relat. Metab. Disord.
26
,
1442
1450
.
De Matteis
R.
,
Zingaretti
M. C.
,
Murano
I.
,
Vitali
A.
,
Frontini
A.
,
Giannulis
I.
,
Barbatelli
G.
,
Marcucci
F.
,
Bordicchia
M.
,
Sarzani
R.
, et al. 
(
2009
).
In vivo physiological transdifferentiation of adult adipose cells
.
Stem Cells
27
,
2761
2768
.
Fantuzzi
G.
,
Faggioni
R.
(
2000
).
Leptin in the regulation of immunity, inflammation, and hematopoiesis
.
J. Leukoc. Biol.
68
,
437
446
.
Feldmann
H. M.
,
Golozoubova
V.
,
Cannon
B.
,
Nedergaard
J.
(
2009
).
UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality
.
Cell Metab.
9
,
203
209
.
Fisher
F. M.
,
Kleiner
S.
,
Douris
N.
,
Fox
E. C.
,
Mepani
R. J.
,
Verdeguer
F.
,
Wu
J.
,
Kharitonenkov
A.
,
Flier
J. S.
,
Maratos-Flier
E.
, et al. 
(
2012
).
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
.
Genes Dev.
26
,
271
281
.
Frontini
A.
,
Cinti
S.
(
2010
).
Distribution and development of brown adipocytes in the murine and human adipose organ
.
Cell Metab.
11
,
253
256
.
Frontini
A.
,
Rousset
S.
,
Cassard-Doulcier
A. M.
,
Zingaretti
C.
,
Ricquier
D.
,
Cinti
S.
(
2007
).
Thymus uncoupling protein 1 is exclusive to typical brown adipocytes and is not found in thymocytes
.
J. Histochem. Cytochem.
55
,
183
189
.
Ghorbani
M.
,
Himms-Hagen
J.
(
1997
).
Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats
.
Int. J. Obes. Relat. Metab. Disord.
21
,
465
475
.
Ghorbani
M.
,
Claus
T. H.
,
Himms-Hagen
J.
(
1997
).
Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a beta3-adrenoceptor agonist
.
Biochem. Pharmacol.
54
,
121
131
.
Giordano
A.
,
Frontini
A.
,
Cinti
S.
(
2008
).
Adipose organ nerves revealed by immunohistochemistry
.
Methods Mol. Biol.
456
,
83
95
.
Gregor
M. F.
,
Hotamisligil
G. S.
(
2011
).
Inflammatory mechanisms in obesity
.
Annu. Rev. Immunol.
29
,
415
445
.
Guerra
C.
,
Koza
R. A.
,
Yamashita
H.
,
Walsh
K.
,
Kozak
L. P.
(
1998
).
Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity
.
J. Clin. Invest.
102
,
412
420
.
Gupta
R. K.
,
Mepani
R. J.
,
Kleiner
S.
,
Lo
J. C.
,
Khandekar
M. J.
,
Cohen
P.
,
Frontini
A.
,
Bhowmick
D. C.
,
Ye
L.
,
Cinti
S.
, et al. 
(
2012
).
Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells
.
Cell Metab.
15
,
230
239
.
Hansen
J. B.
,
Jørgensen
C.
,
Petersen
R. K.
,
Hallenborg
P.
,
De Matteis
R.
,
Bøye
H. A.
,
Petrovic
N.
,
Enerbäck
S.
,
Nedergaard
J.
,
Cinti
S.
, et al. 
(
2004
).
Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation
.
Proc. Natl. Acad. Sci. USA
101
,
4112
4117
.
Hausman
D. B.
,
DiGirolamo
M.
,
Bartness
T. J.
,
Hausman
G. J.
,
Martin
R. J.
(
2001
).
The biology of white adipocyte proliferation
.
Obes. Rev.
2
,
239
254
.
Himms-Hagen
J.
(
1986
).
Brown adipose tissue and cold-acclimation
. In
Brown adipose tissue
(ed.
Trayhurn
P.
,
Nicholls
a. D.
), pp.
214
.
London
:
Edward Arnold
.
Himms-Hagen
J.
,
Melnyk
A.
,
Zingaretti
M. C.
,
Ceresi
E.
,
Barbatelli
G.
,
Cinti
S.
(
2000
).
Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes
.
Am. J. Physiol. Cell Physiol.
279
,
C670
C681
.
Hoffstedt
J.
,
Arner
E.
,
Wahrenberg
H.
,
Andersson
D. P.
,
Qvisth
V.
,
Löfgren
P.
,
Rydén
M.
,
Thörne
A.
,
Wirén
M.
,
Palmér
M.
, et al. 
(
2010
).
Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity
.
Diabetologia
53
,
2496
2503
.
Hondares
E.
,
Rosell
M.
,
Gonzalez
F. J.
,
Giralt
M.
,
Iglesias
R.
,
Villarroya
F.
(
2010
).
Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat
.
Cell Metab.
11
,
206
212
.
Ishibashi
J.
,
Seale
P.
(
2010
).
Medicine. Beige can be slimming
.
Science
328
,
1113
1114
.
Jimenez
M.
,
Barbatelli
G.
,
Allevi
R.
,
Cinti
S.
,
Seydoux
J.
,
Giacobino
J. P.
,
Muzzin
P.
,
Preitner
F.
(
2003
).
Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat
.
Eur. J. Biochem.
270
,
699
705
.
Jimenez-Preitner
M.
,
Berney
X.
,
Uldry
M.
,
Vitali
A.
,
Cinti
S.
,
Ledford
J. G.
,
Thorens
B.
(
2011
).
Plac8 is an inducer of C/EBPß required for brown fat differentiation, thermoregulation, and control of body weight
.
Cell Metab.
14
,
658
670
.
Kiefer
F. W.
,
Vernochet
C.
,
O’Brien
P.
,
Spoerl
S.
,
Brown
J. D.
,
Nallamshetty
S.
,
Zeyda
M.
,
Stulnig
T. M.
,
Cohen
D. E.
,
Kahn
C. R.
, et al. 
(
2012
).
Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue
.
Nat Med.
[Epub ahead of print] doi:.
Kopecky
J.
,
Hodny
Z.
,
Rossmeisl
M.
,
Syrovy
I.
,
Kozak
L. P.
(
1996
).
Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution
.
Am. J. Physiol.
270
,
E768
E775
.
Kuji
I.
,
Imabayashi
E.
,
Minagawa
A.
,
Matsuda
H.
,
Miyauchi
T.
(
2008
).
Brown adipose tissue demonstrating intense FDG uptake in a patient with mediastinal pheochromocytoma
.
Ann. Nucl. Med.
22
,
231
235
.
Lee
Y. H.
,
Petkova
A. P.
,
Mottillo
E. P.
,
Granneman
J. G.
(
2012
).
In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding
.
Cell Metab.
15
,
480
491
.
Leonardsson
G.
,
Steel
J. H.
,
Christian
M.
,
Pocock
V.
,
Milligan
S.
,
Bell
J.
,
So
P. W.
,
Medina-Gomez
G.
,
Vidal-Puig
A.
,
White
R.
, et al. 
(
2004
).
Nuclear receptor corepressor RIP140 regulates fat accumulation
.
Proc. Natl. Acad. Sci. USA
101
,
8437
8442
.
Lowell
B. B.
,
S-Susulic
V.
,
Hamann
A.
,
Lawitts
J. A.
,
Himms-Hagen
J.
,
Boyer
B. B.
,
Kozak
L. P.
,
Flier
J. S.
(
1993
).
Development of obesity in transgenic mice after genetic ablation of brown adipose tissue
.
Nature
366
,
740
742
.
Madsen
L.
,
Pedersen
L. M.
,
Lillefosse
H. H.
,
Fjaere
E.
,
Bronstad
I.
,
Hao
Q.
,
Petersen
R. K.
,
Hallenborg
P.
,
Ma
T.
,
De Matteis
R.
, et al. 
(
2010
).
UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity
.
PLoS ONE
5
,
e11391
.
Masso-Welch
P. A.
,
Darcy
K. M.
,
Stangle-Castor
N. C.
,
Ip
M. M.
(
2000
).
A developmental atlas of rat mammary gland histology
.
J. Mammary Gland Biol. Neoplasia
5
,
165
185
.
Maumus
M.
,
Peyrafitte
J. A.
,
D’Angelo
R.
,
Fournier-Wirth
C.
,
Bouloumié
A.
,
Casteilla
L.
,
Sengenès
C.
,
Bourin
P.
(
2011
).
Native human adipose stromal cells: localization, morphology and phenotype
.
Int. J. Obes.
35
,
1141
1153
.
Mori
M.
,
Nakagami
H.
,
Rodriguez-Araujo
G.
,
Nimura
K.
,
Kaneda
Y.
(
2012
).
Essential role for miR-196a in brown adipogenesis of white fat progenitor cells
.
PLoS Biol.
10
,
e1001314
.
Moro
K.
,
Yamada
T.
,
Tanabe
M.
,
Takeuchi
T.
,
Ikawa
T.
,
Kawamoto
H.
,
Furusawa
J.
,
Ohtani
M.
,
Fujii
H.
,
Koyasu
S.
(
2010
).
Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells
.
Nature
463
,
540
544
.
Morroni
M.
,
Giordano
A.
,
Zingaretti
M. C.
,
Boiani
R.
,
De Matteis
R.
,
Kahn
B. B.
,
Nisoli
E.
,
Tonello
C.
,
Pisoschi
C.
,
Luchetti
M. M.
, et al. 
(
2004
).
Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland
.
Proc. Natl. Acad. Sci. USA
101
,
16801
16806
.
Murano
I.
,
Zingaretti
C. M.
,
Cinti
S.
(
2005
).
The adipose organ of Sv129 mice contains a prevalence of brown adipocytes and shows plasticity after cold exposure
.
Adipocytes
1
,
121
130
.
Murano
I.
,
Barbatelli
G.
,
Parisani
V.
,
Latini
C.
,
Muzzonigro
G.
,
Castellucci
M.
,
Cinti
S.
(
2008
).
Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice
.
J. Lipid Res.
49
,
1562
1568
.
Murano
I.
,
Barbatelli
G.
,
Giordano
A.
,
Cinti
S.
(
2009
).
Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ
.
J. Anat.
214
,
171
178
.
Nechad
M.
(
1986
).
Structure and development of brown adipose tissue
. In
Brown Adipose Tissue
(ed.
Trayhurn
P.
,
Nicholls
D.
),
Baltimore, MD
:
Arnold
.
Nedergaard
J.
,
Bengtsson
T.
,
Cannon
B.
(
2007
).
Unexpected evidence for active brown adipose tissue in adult humans
.
Am. J. Physiol. Endocrinol. Metab.
293
,
E444
E452
.
Oberkofler
H.
,
Dallinger
G.
,
Liu
Y. M.
,
Hell
E.
,
Krempler
F.
,
Patsch
W.
(
1997
).
Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans
.
J. Lipid Res.
38
,
2125
2133
.
Patwari
P.
,
Emilsson
V.
,
Schadt
E. E.
,
Chutkow
W. A.
,
Lee
S.
,
Marsili
A.
,
Zhang
Y.
,
Dobrin
R.
,
Cohen
D. E.
,
Larsen
P. R.
, et al. 
(
2011
).
The arrestin domain-containing 3 protein regulates body mass and energy expenditure
.
Cell Metab.
14
,
671
683
.
Petrovic
N.
,
Walden
T. B.
,
Shabalina
I. G.
,
Timmons
J. A.
,
Cannon
B.
,
Nedergaard
J.
(
2010
).
Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes
.
J. Biol. Chem.
285
,
7153
7164
.
Ricquier
D.
(
2005
).
Respiration uncoupling and metabolism in the control of energy expenditure
.
Proc. Nutr. Soc.
64
,
47
52
.
Saito
M.
,
Okamatsu-Ogura
Y.
,
Matsushita
M.
,
Watanabe
K.
,
Yoneshiro
T.
,
Nio-Kobayashi
J.
,
Iwanaga
T.
,
Miyagawa
M.
,
Kameya
T.
,
Nakada
K.
, et al. 
(
2009
).
High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity
.
Diabetes
58
,
1526
1531
.
Seale
P.
,
Kajimura
S.
,
Yang
W.
,
Chin
S.
,
Rohas
L. M.
,
Uldry
M.
,
Tavernier
G.
,
Langin
D.
,
Spiegelman
B. M.
(
2007
).
Transcriptional control of brown fat determination by PRDM16
.
Cell Metab.
6
,
38
54
.
Seale
P.
,
Bjork
B.
,
Yang
W.
,
Kajimura
S.
,
Chin
S.
,
Kuang
S.
,
Scimè
A.
,
Devarakonda
S.
,
Conroe
H. M.
,
Erdjument-Bromage
H.
, et al. 
(
2008
).
PRDM16 controls a brown fat/skeletal muscle switch
.
Nature
454
,
961
967
.
Seale
P.
,
Conroe
H. M.
,
Estall
J.
,
Kajimura
S.
,
Frontini
A.
,
Ishibashi
J.
,
Cohen
P.
,
Cinti
S.
,
Spiegelman
B. M.
(
2011
).
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
.
J. Clin. Invest.
121
,
96
105
.
Strissel
K. J.
,
Stancheva
Z.
,
Miyoshi
H.
,
Perfield
J. W.
 2nd
,
DeFuria
J.
,
Jick
Z.
,
Greenberg
A. S.
,
Obin
M. S.
(
2007
).
Adipocyte death, adipose tissue remodeling, and obesity complications
.
Diabetes
56
,
2910
2918
.
Sun
L.
,
Xie
H.
,
Mori
M. A.
,
Alexander
R.
,
Yuan
B.
,
Hattangadi
S. M.
,
Liu
Q.
,
Kahn
C. R.
,
Lodish
H. F.
(
2011
).
Mir193b-365 is essential for brown fat differentiation
.
Nat. Cell Biol.
13
,
958
965
.
Timmons
J. A.
,
Wennmalm
K.
,
Larsson
O.
,
Walden
T. B.
,
Lassmann
T.
,
Petrovic
N.
,
Hamilton
D. L.
,
Gimeno
R. E.
,
Wahlestedt
C.
,
Baar
K.
, et al. 
(
2007
).
Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages
.
Proc. Natl. Acad. Sci. USA
104
,
4401
4406
.
Toseland
C. D.
,
Campbell
S.
,
Francis
I.
,
Bugelski
P. J.
,
Mehdi
N.
(
2001
).
Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat
.
Diabetes Obes. Metab.
3
,
163
170
.
Tran
K. V.
,
Gealekman
O.
,
Frontini
A.
,
Zingaretti
M. C.
,
Morroni
M.
,
Giordano
A.
,
Smorlesi
A.
,
Perugini
J.
,
De Matteis
R.
,
Sbarbati
A.
, et al. 
(
2012
).
The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells
.
Cell Metab.
15
,
222
229
.
Tseng
Y. H.
,
Kokkotou
E.
,
Schulz
T. J.
,
Huang
T. L.
,
Winnay
J. N.
,
Taniguchi
C. M.
,
Tran
T. T.
,
Suzuki
R.
,
Espinoza
D. O.
,
Yamamoto
Y.
, et al. 
(
2008
).
New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure
.
Nature
454
,
1000
1004
.
Tsukiyama-Kohara
K.
,
Poulin
F.
,
Kohara
M.
,
DeMaria
C. T.
,
Cheng
A.
,
Wu
Z.
,
Gingras
A. C.
,
Katsume
A.
,
Elchebly
M.
,
Spiegelman
B. M.
, et al. 
(
2001
).
Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1
.
Nat. Med.
7
,
1128
1132
.
van Marken Lichtenbelt
W. D.
,
Vanhommerig
J. W.
,
Smulders
N. M.
,
Drossaerts
J. M.
,
Kemerink
G. J.
,
Bouvy
N. D.
,
Schrauwen
P.
,
Teule
G. J.
(
2009
).
Cold-activated brown adipose tissue in healthy men
.
N. Engl. J. Med.
360
,
1500
1508
.
Vegiopoulos
A.
,
Müller-Decker
K.
,
Strzoda
D.
,
Schmitt
I.
,
Chichelnitskiy
E.
,
Ostertag
A.
,
Berriel Diaz
M.
,
Rozman
J.
,
Hrabe de Angelis
M.
,
Nüsing
R. M.
, et al. 
(
2010
).
Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes
.
Science
328
,
1158
1161
.
Virtanen
K. A.
,
Lidell
M. E.
,
Orava
J.
,
Heglind
M.
,
Westergren
R.
,
Niemi
T.
,
Taittonen
M.
,
Laine
J.
,
Savisto
N. J.
,
Enerbäck
S.
, et al. 
(
2009
).
Functional brown adipose tissue in healthy adults
.
N. Engl. J. Med.
360
,
1518
1525
.
Virtue
S.
,
Vidal-Puig
A.
(
2010
).
Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective
.
Biochim. Biophys. Acta
1801
,
338
349
.
Vitali
A.
,
Murano
I.
,
Zingaretti
M. C.
,
Frontini
A.
,
Ricquier
D.
,
Cinti
S.
(
2012
).
The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes
.
J. Lipid Res.
53
,
619
629
.
Waldén
T. B.
,
Hansen
I. R.
,
Timmons
J. A.
,
Cannon
B.
,
Nedergaard
J.
(
2012
).
Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues
.
Am. J. Physiol. Endocrinol. Metab.
302
,
E19
E31
.
Weisberg
S. P.
,
McCann
D.
,
Desai
M.
,
Rosenbaum
M.
,
Leibel
R. L.
,
Ferrante
A. W.
 Jr
(
2003
).
Obesity is associated with macrophage accumulation in adipose tissue
.
J. Clin. Invest.
112
,
1796
1808
.
Wood
I. S.
,
de Heredia
F. P.
,
Wang
B.
,
Trayhurn
P.
(
2009
).
Cellular hypoxia and adipose tissue dysfunction in obesity
.
Proc. Nutr. Soc.
68
,
370
377
.
Xu
H.
,
Barnes
G. T.
,
Yang
Q.
,
Tan
G.
,
Yang
D.
,
Chou
C. J.
,
Sole
J.
,
Nichols
A.
,
Ross
J. S.
,
Tartaglia
L. A.
, et al. 
(
2003
).
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
.
J. Clin. Invest.
112
,
1821
1830
.
Yadav
H.
,
Quijano
C.
,
Kamaraju
A. K.
,
Gavrilova
O.
,
Malek
R.
,
Chen
W.
,
Zerfas
P.
,
Zhigang
D.
,
Wright
E. C.
,
Stuelten
C.
, et al. 
(
2011
).
Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling
.
Cell Metab.
14
,
67
79
.
Zingaretti
M. C.
,
Crosta
F.
,
Vitali
A.
,
Guerrieri
M.
,
Frontini
A.
,
Cannon
B.
,
Nedergaard
J.
,
Cinti
S.
(
2009
).
The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue
.
FASEB J.
23
,
3113
3120
.

COMPETING INTERESTS

The authors declare that they do not have any competing or financial interests.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.