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International Journal of Obesity (2010) 34, S59–S66
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ORIGINAL ARTICLE
Determinants of brown adipocyte development and
thermogenesis
D Richard1, AC Carpentier2, G Doré1, V Ouellet1 and F Picard1
1
Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, et Groupe interdisciplinaire
de Recherche sur l’Obésité de l’Université Laval, Québec, Canada and 2Centre de recherche clinique Étienne-Le Bel du
Centre hospitalier universitaire de Sherbrooke, Québec, Canada
The brown adipocyte is a thermogenic cell. Its thermogenic potential is conferred by uncoupling protein-1, which ‘uncouples’
adenosine triphosphate synthesis from energy substrate oxidation. Brown fat cells in so-called classical brown adipose tissue
(BAT) share their origin with myogenic factor-5-expressing myoblasts. The development of myocyte/brown adipocyte
progenitor cells into a brown adipocyte lineage is apparently triggered by bone morphogenetic protein-7, which stimulates
inducers of brown fat cell differentiation, such as PRD1-BF1-RIZ1 homologous domain-containing-16 and peroxisome
proliferator-activated receptor-g co-activator-1-a. The control of brown fat cell development and activity is physiologically
ensured by the sympathetic nervous system (SNS), which densely innervates BAT. SNS-mediated thermogenesis is largely
governed by hypothalamic and brainstem neurons. With regard to energy balance, the leptin–melanocortin pathway appears to
be a major factor in controlling brown adipocyte thermogenesis. The involvement of this homeostatic pathway further supports
the role of the brown adipocyte in energy balance regulation. The interest for the brown fat cell and its potential role in energy
balance has been further rejuvenated recently by the demonstration that BAT can be present in substantial amounts in humans,
in contrast to what has always been thought. Positron emission tomography/computed tomography scanning investigations
have indeed revealed the presence in humans of important neck and shoulder cold-activable BAT depots, in particular, in young,
lean and female subjects. This short review summarizes recent progress made in the biology of the brown fat cell and focuses on
the determinants of the brown adipocyte development and activity.
International Journal of Obesity (2010) 34, S59–S66; doi:10.1038/ijo.2010.241
Keywords: brown adipose tissue; thermogenesis; uncoupling protein-1; brown adipocyte; brown adipocyte development
Introduction
Brown adipose tissue (BAT) is a specialized heat-producing
tissue. Its existence was revealed in the middle of the
sixteenth century by the Swiss naturalist Conrad Gesner,1
who described BAT as being ‘neither fat nor flesh’ (nec
pinguitudo nec caro). BAT is particularly abundant in rodents,
such as rats, mice, hamsters, and gerbils, in which it is
apparent as discrete small depots mostly found in the
interscapular, subscapular, axillary, perirenal and periaortic
regions (the so-called classical BAT depots). BAT is mainly
recognized for its ability to generate heat. The thermogenic
capacity of this tissue is such that it allows small mammals to
live below their thermoneutral temperature without having
to rely on muscle-mediated shivering thermogenesis to
Correspondence: Dr D Richard, Centre de recherche de l’Institut universitaire
de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy,
Québec, Canada G1 V 4G5.
E-mail: [email protected]
maintain a normal core temperature.2,3 Studies carried out
at the end of the 1970s demonstrated that BAT could
contribute to more than 60% of non-shivering thermogenesis induced by noradrenaline in cold-adapted rats.4 The
extraordinary thermogenic protential of the brown adipocyte is conferred by uncoupling protein-1 (UCP1). UCP1 is a
mitochondrial protein uniquely found in brown adipocytes.
It represents the ultimate phenotypic signature of this cell.5,6
Once activated, UCP1 disconnects (uncouples) the mitochondrial oxidation of fatty acids from adenosine triphosphate (ATP) synthesis, thereby initiating heat production.
The recent demonstration that BAT can exist in substantial
amount in humans7–12 has rejuvenated the interest for BAT
and for BAT thermogenesis in energy balance regulation.
This renewed appeal for BAT has been further aroused by the
discovery that brown fat cells in typical BAT (in contrast
to brown fat cells in white adipose tissue (WAT)) do not
originate from white adipocyte precursors but from myocyte
progenitor cells13–17 and by the description from transneuronal viral retrograde tract tracing studies18–20 of numerous
Brown adipocyte development and thermogenesis
D Richard et al
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brain pathways that drive the sympathetic nervous system
(SNS) outflow to BAT.
This short review summarizes the recent progress made in
the biology of the brown adipocyte. The focus is on (i) the
cellular biology of brown (UCP1 expressing) adipocyte
in BAT and WAT depots, (ii) the neural control of BAT
thermogenesis and (iii) the determinants of BAT prevalence
in humans.
The cellular biology of the brown fat cell
Although white fat cells are round and comprise a single
lipid droplet surrounded by a small amount of cytoplasm
and few mitochondria, brown adipocytes are polygonal in
appearance and contain numerous small lipid vacuoles,
encircled by a perceptible cytoplasm and abundant and welldeveloped mitochondria packed with laminar cristae.6,21,22
Brown adipocytes make up classical BAT depots and can
also develop in relative abundance in WAT upon adrenergic
stimulation.23,24
Brown adipocytes in so-called classical BAT depots
share their origin with myocytes
Evidence has accumulated in recent years to suggest that
brown fat cells in classical BAT depots do not share their origin
with white adipocytes, but rather with myocytes.13–17,25 Atit
et al.,13 using a genetic fate mapping approach, demonstrated that engrailed-1 (En1)-expressing cells of the dermomyotome are the primordia of not only the dermis and
muscle but also interscapular BAT. Concomitantly, Timmons
et al.15 reported that brown preadipocytes (from those
classical BAT depots) exhibit a myogenic transcriptional
profile, whereas Seale et al.,14,17 Tseng et al.16 and Kajimura
et al.25 decoded the sequence of events leading to brown fat
differentiation from myogenic factor-5-expressing myoblasts. Seale et al.14,17 described PRD1-BF1-RIZ1 homologous
domain-containing-16 (PRDM16) as a major transcription
factor in BAT adipogenesis. PRDM16 has a key role in
triggering brown adipocyte differentiation, mitochondrial
biogenesis and expression of UCP1. Meanwhile, Tseng et al.16
demonstrated that bone morphogenetic protein-7 (BMP7)
could trigger the commitment of mesenchymal progenitor
cells to a brown adipocyte lineage, while inducing early
regulators of brown fat such as PRDM16 and peroxisome
proliferator-activated receptor-g (PPARg) co-activator-1-a
(PGC1a). Similar to PRDM16, PGC-1a is a PPARg transcriptional co-activator that confers the brown adipocyte with its
energy-burning phenotype.26,27 More recently, Kajimura
et al.25 demonstrated that PRDM16 controls brown adipogenesis from myoblasts by forming a transcriptional complex with the active form of CCAAT/enhancer-binding
protein-b (C/EBPb). Together with C/EBPa and C/EBPd,
C/EBPb contributes to the establishment of the brown fat
lineage through sustained transactivation of PPARg and
International Journal of Obesity
brown adipocyte genes.28 PPARg is regarded as a master
protein for adipocyte differentiation (be they white or
brown) from preadipocytes.29–31 Finally, further supporting
the notion that brown adipocytes and myocytes derive from
a common cell lineage, the studies by Forner et al.32 and
Walden et al.33 respectively, showed that the proteomics of
brown fat corresponded more to that of muscle than to that
of white fat, and that the muscle microRNAs (myomiR) miR1, miR-133a and miR-206 were expressed in brown, but not
white adipocytes. The term ‘adipomyocyte’ has been judiciously coined by Cannon et al.34 to designate the brown
adipocytes in the classical BAT depots.
Brown fat cells in WAT have their own origin
Notably, brown adipocytes can also develop in typical WAT,
where they might contribute to thermogenesis.35 Within
WAT, brown fat cells develop on specific stimuli, such as
PPARg agonism21,36 and the adrenergic activation induced
by either cold exposure37,38 or by treatment with b3
adrenergic receptor agonists.39
The origin of the brown adipocytes in WAT is still
uncertain, as it is not clear whether these cells develop
through the differentiation of specific precursors, the
differentiation/transdifferentiation of white preadipocytes
or the process of transdifferentiation of already differentiated
cells.22,24,40,41 According to Cinti,22 white to brown
adipocytes transdifferentiation on adrenergic stimulation
would occur gradually.22 The mature white adipocyte
would first transform into a multilocular cell, first devoid
of UCP1, which would eventually evolve into an UCP1positive brown fat cell. In addition to being supported
morphologically, the transdifferentiation hypothesis is also
corroborated by the observation that the total number of
adipocytes (white plus brown) in a given WAT depot does
not change after adrenergic stimulation (cold exposure),
whereas the proportion of brown adipocytes significantly
increases,42 and by the finding that the newly emerging
brown adipocytes in WAT following b3-adrenergic stimulation are 5-bromo-2-deoxyuridine negative (indicating a
low mitotic index).38 However, the transdifferentiation
hypothesis is still disputed. Petrovic et al.41 failed to provide
any evidence of the transformation of mature white
adipocytes into UCP1-positive adipocytes. Those authors
rather proposed that brown adipocytes found in typical WAT
would represent a subset of adipocyes with a developmental
origin which is different from brown adipocytes found in
classical BAT. WAT brown adipocytes, which would on
adrenergic stimulation convincingly express PGC1a and
UCP1, apparently express less PRDM16 than BAT brown
adipocytes, even upon stimulation with a PPARg agonist.41
In addition, they do not transcribe muscle-specific microRNAs, such as miR-206, whereas they express Homeobox-C9
(Hoxc9), a gene characterizing classic white adipocytes.
Those cells have been designated as ‘brite adipocytes’
(brown-in-white).41
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D Richard et al
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UCP1 provides the brown adipocyte with its extraordinary
thermogenic potential
UCPI is a six-domain transmembrane protein that is located
in the inner membrane of the BAT mitochondrion.2,5 It is,
together with UCP2 and UCP3, a member of the UCP
superfamily, within which it is the only thermogenic
protein43 and likely the only true UCP.44 Studies conducted
in UCP1-deficient mice have indisputably revealed the
importance of UCP1 in non-shivering thermoregulatory
thermogenesis,45 whereas studies conducted in UCP2- and
UCP3-ablated mice have proved to be unpersuasive in
revealing a thermogenic function for UCP2 and UCP3.46
UCP1 uncouples ATP synthesis from mitochondrial substrate oxidation.6,47–49 Brown adipocyte-derived fatty acids,
which originate from the breakdown of intracellular triglycerides in response to b-adrenergic activation, constitute the
main energy substrate for BAT heat production. They
additionally activate UCP1 by overriding the inhibitory
action of purine nucleotides on UCP1.6,47–49 Fatty acid
oxidation generates nicotinamide adenine dinucleotide and
flavin adenine dinucleotide, which furnish electrons that are
ultimately transported from one to another protein complex
making up the mitochondrial respiratory chain (electron
transport chain). This electron transport is coupled with the
pumping of protons from the mitochondrial matrix to the
intermembrane space, which establishes the proton gradient
across the inner mitochondrial membrane. In most cells, the
mitochondrial electrochemical proton gradient finds its way
through the proton-conducting unit of the ATP synthase
assembly, thereby producing the protonmotive force to drive
phosphorylation of ADP to ATP. In stimulated brown
adipocytes, the proton gradient is dissipated through the
alternative UCP1 proton channel and is prevented from
accessing the ATP synthase complex. As a consequence, ATP
is barely synthesized and seemingly does not accumulate to
decelerate the activated catabolic cascades through which
heat is necessarily produced.47 UCP1 thus serves as a conduit
to dissipate the ATP-generating electrochemical proton
gradient that builds up across the mitochondrial inner
membrane concomitantly with electron transport during
BAT oxidation of fatty acids.
UCP1 expression is physiologically enhanced by adrenergic stimulation (Figure 1). It can also pharmacologically be
induced by PPARg agonists.36 The b3-adrenergic receptor, at
least in rodents, is regarded as the key adrenergic receptor
triggering BAT activity.50 The b-adrenergic pathway prompts
the production of cyclic adenosine monophosphate, which
in turn activates protein kinase-A-dependent phophorylation of p38a mitogen-activated protein kinase (p38a map
kinase). p38a map kinase phosphorylates activating-transcription factor-2 to induce PGC1a transcription, a key node
in catecholamine-induced thermogenesis. PGC-1a is directly
involved in the stimulation of UCP1 expression through its
ability to co-activate PPARg.26 In addition, PGC1a directly
interacts with nuclear respiratory factors 1 and 2 (NRF1and
NRF2) to stimulate de novo mitochondrion synthesis, and
with different protein complexes (including PPARs) to
induce Ucp1. Ucp1’s promoter contains many distinct binding sites, allowing a wide range of proteins to influence its
transcription. These binding sites include cyclic adenosine
monophosphate, thyroid, PPAR, retinoic acid-response elements (respectively abbreviated as CRE, TRE, PPRE, RARE).
Retinoid X receptor-a is a nuclear receptor that acts in the
brown adipocyte as a partner of, for instance, PPARg and
thyroid receptor-b for heterodimers. b-Adrenergic activation
upregulates levels of CRE, PPARg, thyroid receptor-b, which
all contribute to increase Ucp1’s promoter transactivation.51,52 In addition, BMP7 would stimulate PRDM16
expression, which then would activate PGC1a and UCP1,
leading to an increase in thermogenesis. The binding of liver
X receptor-a and its co-repressor nuclear receptor interacting
protein-1 (known as RIP140) to PPARg would block the
transcriptional activity of PPARg by dislocating the PPARg/
PGC-1a complex off the PPARg-response element53 on the
Ucp1 promoter.
The control of the brown fat cell activity
Brown adipocytes, in BAT depots in particular, are richly
innervated by SNS efferents.54,55 The release by SNS nerves of
noradrenaline in the vicinity of the adipocytes not only
enhances thermogenic activity but also increases the
capacity (synthesis of UCP1, accessory thermogenic proteins,
mitochondria) of the brown fat cell to produce heat. SNS
activation is the physiological trigger of brown adipocyte
thermogenesis.6 Conditions such as cold exposure or
overfeeding increase noradrenaline turnover rate in BAT.56
Consistently, those conditions do not produce any thermogenic activity in mice lacking b-adrenoreceptors (b-less
mice).57–59
Clusters of neurons from several brain nuclei are implicated
in the thermoregulation control brown adipocyte activity.18 In
addition, most energy-balance regulation centers modulate
SNS-mediated thermogenesis in brown fat cells.60 The control
of BAT activity is basically ensured by the ‘autonomic’ brain
and involves hypothalamic nuclei, such as the median
preoptic nucleus, arcuate nucleus (ARC), retrochiasmatic area,
paraventricular nucleus, lateral hypothalamus, dorsomedial
hypothalamus, and a significant number of brainstem nuclei
including the periaqueductal gray, lateral paragigantocellular
nucleus and raphe nuclei.18,60–62
The leptin–melanocortin pathway is a major controller
of brown adipocyte thermogenesis
One of the most important brain entities involved in brown
adipocyte thermogenesis, with reference to energy balance,
is the melanocortin system.63–66 This system comprises
proopiomelanocortin (POMC) neurons, which essentially
originate from the ARC and which also express cocaine
and amphetamine-regulated transcript (CART). POMC postInternational Journal of Obesity
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Catecholamines
cold
Adenylyl Cyclase
βARs
AKAP
β
γ
RIIβ2
Gα
J1P2/IB2
JIP4 ?
GEFs
C
C
P P
Rac1
cyclic AMP
P38α map
kinase
P P
MKK3
MKKK
P P
Activated PKA
?
?
PRDM16
BMP7
Thermogenesis
?
P
Sirt1 ?
Activation of
mitochondrial
genes
NRF1
NRF2
P
ATF2 ATF2
PGC1α
CRE2
PGC1α
PPARγ
UCP1
PPARγ
RXRα
T3
P P P
PGC1α
PRDM16
PPRE
RXRα
cAMP
PRDM16 ?
CRE
TRE/RARE
T4
ATF2
NFE2
P
ATF2
?
P
TRβ
CRE4
RXRα
CREB
CREB
PRDM16?
NFE212
UCP1
Nucleus
DIO2
RIP140
LXRα
PPRE
Figure 1 Catecholamine-induced thermogenesis in the brown adipocyte. Conditions such as cold exposure or overfeeding stimulates the sympathetic nervous
system (SNS), which induces the thermogenic activity and capacity of the brown fat cell. Noradrenaline binds to b-adrenergic receptors present on the outer
membrane of the cell, leading to cyclic adenosine monophosphate (cAMP) release. cAMP activates PKA, ultimately triggering phosphorylation of p38a map kinase.
p38a map kinase directly phosphorylates ATF2 to induce PGC1a transcription, a key node in the catecholamine-induced thermogenesis. PGC1a directly interact with
NRF1 and NRF2 to stimulate de novo mitochondria and with different protein complexes (including PPARs) to induce the transcription of UCP1. The UCP1 promoter
contains many distinct binding sites, allowing a wide range of protein to influence its transcription. BMP7 stimulates PRDM16 expression, which then activates the
promoter of PGC1a and UCP1, leading to increased thermogenesis. The binding of LXRa and its co-repressor RIP140 to PPARg can inhibit UCP1 production by
disrupting PPARg from its complex. See text for more details. ATF, activating transcription factor; bARs, b-adrenergic receptors; BMP7, bone morphogenetic protein7; CREB, cAMP-response element-binding protein; NRF, nuclear respiratory factor; p38a map kinase, p38a mitogen-activated protein kinase; PGC1a, Peroxisome
proliferator-activated receptor-g co-activator 1-a; PKA, protein kinase A; PPARg, peroxisome proliferator-activated receptor-g; PPRE, PPARg-response element;
PRDM16, PRD1-BF1-RIZ1 homologous domain-containing-16; RXRa, retinoid X receptor; RARE, retinoid X receptor-response element; RIP140, nuclear receptorinteracting protein-1; TRb, thyroid receptor-b; TRE, TR-response element.
translational cleavage frees the peptidergic fragment
a-melanocyte-stimulating hormone. a-Melanocyte-stimulating hormone is a catabolic peptide binding to the melanocortin-3 and 4 receptors (MC3R and MC4R), the two main
receptors of the brain metabolic melanocortin system. MC4R
deficiency causes massive and widespread body fat deposition resulting from not only an increase in energy intake but
also a decrease in thermogenesis.66,67 In contrast, MC4R
agonists, such as Melanotan II (MTIIFa synthetic analog of amelanocyte-stimulating hormone), induce UCP1 in BAT68,69
while enhancing SNS discharge to both adipose tissues.69
Song et al.19,70 and Voss-Andreae et al.71 have clearly
International Journal of Obesity
established a connection between the MC4R-containing
neurons and BAT or WAT. We even observed in some brain
nuclei (paraventricular nucleus, raphe pallidus and lateral
paragigantocellular nucleus) that more than 80% of the
neurons projecting to BAT express the MC4R.19
The activity of the melanocortin system is modulated by
the adipose-derived hormone leptin.72,73 Leptin is a catabolic hormone whose action is partly exerted at the levels of
the ARC by the signal transducer and activator of transcription-3 signaling cascade. Leptin modulates the activity of the
melanocortin system through directly reducing the synthesis
of POMC and indirectly blunting the synthesis of neuropep-
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D Richard et al
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tide Y and agouti-related protein, the latter being an
endogenous MC4R antagonist/inverse agonist.74
There is evidence that the leptin receptor long form
(LepRb) and MC4R could be part of the same homeostatic
pathway controlling SNS activity in adipose tissues. Absence
of the MC4R has been shown to compromise the ability of
leptin (be it injected centrally or peripherally) to increase
UCP1 expression in BAT and WAT.75 At least three pathways
could depend on the MC4R, emphasizing the importance of
the leptin–melanocortin pathway in brown adipocyte activity. A first pathway would consist of LepRb/POMC/CART
neurons in the ARC that project to the paraventricular
nucleus to form synapses with MC4R-expressing neurons
that directly descend to the intermediolateral (IML) cell
column in the lateral horn of the spinal cord to synapse with
SNS preganglionic neurons.76 The descending division of the
paraventricular nucleus comprises a very high percentage of
neurons connected to BAT and WAT.19,70 These neurons
could be oxytocin neurons,77 even though this has not been
clearly demonstrated. A second pathway would consist of
LepRb/POMC/CART neurons in the retrochiasmatic area that
project to the IML to form synapses with MC4R-expressing
SNS preganglionic neurons.78 The MC4R is indeed expressed
at the level of the IML on SNS preganglionic neurons.79 A
third pathway would consist of LepRb/POMC/CART neurons
in the ARC that project directly or indirectly (through a
neuronal relay in the periaqueductal gray) to the raphe
pallidus to ultimately form synapses with MC4R-expressing
SNS premotor neurons, most likely serotonin (5-HT) neurons80 involved in the control of BAT (and possibly WAT)
thermogenesis.81 MTII injections in the raphe pallidus
increased BAT SNS activity.82
On the other hand, the possibility that leptin can also
control brown adipocyte activity independently of the
MC4R cannot, of course, be excluded.83 A MC4R-independent pathway could consist of LepRb/melanin-concentrating
hormone/orexin neurons in the lateral hypothalamus that
project directly to the IML to control the SNS outflow to BAT
and WAT. Melanin-concentrating hormone- and orexinexpressing neurons project to the IML.84,85
iodothyronine deiodinase, PGC1a, PRDM16 and b3-adrenergic receptor,10 which are all key factors in BAT thermogenesis. The cervical/supraclavicular UCP1-positive cells display
the classical morphology of brown fat cells with numerous
cytoplasmic uniform fat vacuoles and abundant mitochondria.7,8 They are highly vascularized and densely innervated
with nerve fibers immunopositive for tyrosine hydroxylase,
indicating a rich sympathetic innervation.7
Positron emission tomography/computed tomography
18
F-FDG scanning reveals in humans that the main BAT
depots are cervical/supraclavicular, paravertebral, mediastinal and perirenal (Figure 2). The cervical/supraclavicular
depot appears to be the most prevalent and the one with the
highest 18F-FDG uptake activity following exposure to
cold.10 The prevalence of 18F-FDG uptake in adipose tissue
(i) increases with exposure to below thermoneutral temperature;8,11,88–90 (ii) is higher in women than men;8 (iii)
decreases with age;7,8,88 and (iv) is inversely correlated with
body mass index and body fat content.7,8,88 The prevalence
Determinants of human BAT thermogenesis
In the last decade, nuclear medicine strongly challenged the
belief that adult humans carry only vestiges of BAT.86,87
Indeed, positron emission tomography/computed tomography scanning investigations, using the glucose analog
18
F-fluorodeoxyglucose (18F-FDG), revealed symmetrical
18
F-FDG uptake by fat depots in the cervical/supraclavicular,
paravertebral, mediastinal and perirenal regions of the body.
Those fat depots were a posteriori demonstrated to have
all the histological characteristics of brown fat sites.7–10
18
F-FDG-detected fat expresses UCP1 (mRNA and protein)
and mRNAs encoding other proteins, such as type II
Figure 2 Brown adipose tissue (BAT) in humans demonstrated by positron
emission tomography (PET) after intravenous injection of 18F-fluorodeoxyglucose (18F-FDG). Fused PET/computed tomography images reveals cervical/
supraclavicular, paravertebral, mediastinal and perirenal 18F-FDG sites that
have been confirmed to be brown fat.
International Journal of Obesity
Brown adipocyte development and thermogenesis
D Richard et al
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that regard, transneuronal viral retrograde tract tracing
studies18–20 have been particularly instrumental in identifying major thermogenic brain sites. Finally, the conclusive
proof from positron emission tomography/computed tomography scanning investigations that BAT can be present in
substantial amounts in adult human individuals has
emerged as the finding that has contributed the most to
the rejuvenated interest in BAT.86 The observations that 18FFDG uptake by fat tissue is stimulated by below thermoneutral temperatures8,11,88–90 and is blunted by aging,
fatness and b-blockers support the prediction of a brown
adipocyte involvement in energy balance regulation.91
Conflict of interest
Figure 3 Determinants of 18F-FDG uptake in BAT. Acute 18F-FDG uptake in
BAT necessitates an SNS-mediated BAT activation ( þ ) likely driven by a below
heat-neutral temperature or other potential BAT activators. Factors such as
young age or chronic exposure to a cold environment (as it is likely to occur in
winter) could enhance BAT capacity for thermogenesis (BAT mass, BAT
mitochondria content, BAT UCP1 content). The larger the BAT capacity, the
higher would be the 18F-FDG uptake on a given activation. Low body mass
index or absence of diabetes (or other factors associated with those
conditions) could also enhance BAT capacity. Having a higher temperature
threshold than men for thermogenesis, women would more readily respond
to cold. Reproduced from reference Ouellet et al.92 (with the permission of
J Clin Endocrinol Metab; Copyright 2010, The Endocrine Society).
of BAT 18F-FDG uptake is also reduced in diabetic patients8
and decreases in patients taking b-blockers.8 Figure 3
tentatively illustrates the main determinants of 18F-FDG
uptake in BAT of adult humans.
Conclusion
Several recent investigations have raised interest in the
brown adipocyte. This thermogenic cell is found in adipose
tissues and its origin depends on the adipose tissue depot
type. The hypothesis that brown fat cells in classical BAT
share their origin with muscle cells has driven many elegant
series of investigations.13–17,25 Meanwhile, the intriguing
origin of the brown fat cell in WAT has also been under
scrutiny,22,24,41 but there is as yet no clear answer as to
whether the latter emerges through the differentiation of
specific precursors, the differentiation/transdifferentiation
of white preadipocytes or the process of transdifferentiation
of already differentiated cells.22,24,40,41 However, it appears
clear that the origin of brown adipocytes in classical WAT is
distinct from that of brown adipocytes in classical BAT. The
renewed interest for the brown adipocyte has also been
driven by all those studies aimed at disentangling the brain
circuits controlling BAT and WAT metabolic activities. In
International Journal of Obesity
ACC has received lecture fees from Pfizer, grant support from
GlaxoSmithKline, Pfizer, Philips, Merck and Co. and Amsterdam Molecular Therapeutics, and holds two patents
related to this subject area. The remaining authors have
declared no conflict of interest.
References
1 Gesner C. Medici Tigurini Historiae Animalium Liber I de Quadrupedibusuiuiparis.
2 Klingenspor M. Cold-induced recruitment of brown adipose
tissue thermogenesis. Exp Physiol 2003; 88: 141–148.
3 Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J 1990; 4: 2890–2898.
4 Foster DO, Frydman ML. Tissue distribution of cold-induced
thermogenesis in conscious warm- or cold-acclimated rats
reevaluated from changes in tissue blood flow: the dominant
role of brown adipose tissue in the replacement of shivering by
nonshivering thermogenesis. Can J Physiol Pharmacol 1979; 57:
257–270.
5 Ricquier D. Respiration uncoupling and metabolism in the
control of energy expenditure. Proc Nutr Soc 2005; 64: 47–52.
6 Cannon B, Nedergaard J. Brown adipose tissue: function and
physiological significance. Physiol Rev 2004; 84: 277–359.
7 Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon
B et al. The presence of UCP1 demonstrates that metabolically
active adipose tissue in the neck of adult humans truly represents
brown adipose tissue. FASEB J 2009; 23: 3113–3120.
8 Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB
et al. Identification and importance of brown adipose tissue in
adult humans. N Engl J Med 2009; 360: 1509–1517.
9 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM,
Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated
brown adipose tissue in healthy men. N Engl J Med 2009; 360:
1500–1508.
10 Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R,
Niemi T et al. Functional brown adipose tissue in healthy adults.
N Engl J Med 2009; 360: 1518–1525.
11 Cohade C, Mourtzikos KA, Wahl RL. ‘USA-Fat’: prevalence
is related to ambient outdoor temperature-evaluation with
18F-FDG PET/CT. J Nucl Med 2003; 44: 1267–1270.
12 Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat (00 USA-Fat00 ): description on 18F-FDG PET/CT.
J Nucl Med 2003; 44: 170–176.
13 Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL
et al. Beta-catenin activation is necessary and sufficient to
Brown adipocyte development and thermogenesis
D Richard et al
S65
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
specify the dorsal dermal fate in the mouse. Dev Biol 2006; 296:
164–176.
Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M et al.
Transcriptional control of brown fat determination by PRDM16.
Cell Metab 2007; 6: 38–54.
Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T,
Petrovic N et al. Myogenic gene expression signature
establishes that brown and white adipocytes originate
from distinct cell lineages. Proc Natl Acad Sci USA 2007; 104:
4401–4406.
Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN,
Taniguchi CM et al. New role of bone morphogenetic protein 7
in brown adipogenesis and energy expenditure. Nature 2008; 454:
1000–1004.
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S et al.
PRDM16 controls a brown fat/skeletal muscle switch. Nature
2008; 454: 961–967.
Morrison SF, Nakamura K, Madden CJ. Central control of
thermogenesis in mammals. Exp Physiol 2008; 93: 773–797.
Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D,
Bartness TJ. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical
and functional evidence. Am J Physiol Regul Integr Comp Physiol
2008; 295: R417–R428.
Bartness TJ, Song CK. Brain-adipose tissue neural crosstalk.
Physiol Behav 2007; 91: 343–351.
Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its
metabolic role. Int J Biochem Cell Biol 2004; 36: 2098–2104.
Cinti S. Reversible physiological transdifferentiation in the
adipose organ. Proc Nutr Soc 2009; 68: 340–349.
Cinti S. The adipose organ: morphological perspectives of adipose
tissues. Proc Nutr Soc 2001; 60: 319–328.
Cinti S. Transdifferentiation properties of adipocytes in
the Adipose Organ. Am J Physiol Endocrinol Metab 2009; 297:
E977–E986.
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV,
Gygi SP et al. Initiation of myoblast to brown fat switch by a
PRDM16-C/EBP-beta transcriptional complex. Nature 2009; 460:
1154–1158.
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman
BM. A cold-inducible coactivator of nuclear receptors linked to
adaptive thermogenesis. Cell 1998; 92: 829–839.
Wu Z, Boss O. Targeting PGC-1 alpha to control energy homeostasis. Expert Opin Ther Targets 2007; 11: 1329–1338.
Karamanlidis G, Karamitri A, Docherty K, Hazlerigg DG, Lomax
MA. C/EBPbeta reprograms white 3T3-L1 preadipocytes to a
Brown adipocyte pattern of gene expression. J Biol Chem 2007;
282: 24660–24669.
Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology
of PPARgamma. Annu Rev Biochem 2008; 77: 289–312.
Lefterova MI, Lazar MA. New developments in adipogenesis.
Trends Endocrinol Metab 2009; 20: 107–114.
Fruhbeck G, Becerril S, Sainz N, Garrastachu P, Garcia-Velloso MJ.
BAT: a new target for human obesity? Trends Pharmacol Sci 2009;
30: 387–396.
Forner F, Kumar C, Luber CA, Fromme T, Klingenspor M,
Mann M. Proteome differences between brown and white fat
mitochondria reveal specialized metabolic functions. Cell Metab
2009; 10: 324–335.
Walden TB, Timmons JA, Keller P, Nedergaard J, Cannon B.
Distinct expression of muscle-specific microRNAs (myomirs) in
brown adipocytes. J Cell Physiol 2009; 218: 444–449.
Cannon B, Nedergaard J. Developmental biology: neither fat nor
flesh. Nature 2008; 454: 947–948.
Kozak LP, Anunciado-Koza R. UCP1: its involvement and utility
in obesity. Int J Obes (Lond) 2008; 32 (Suppl 7): S32–S38.
Nedergaard J, Petrovic N, Lindgren EM, Jacobsson A, Cannon B.
PPARgamma in the control of brown adipocyte differentiation.
Biochim Biophys Acta 2005; 1740: 293–304.
37 Granneman JG, Li P, Zhu Z, Lu Y. Metabolic and cellular plasticity
in white adipose tissue I: effects of beta3-adrenergic receptor
activation. Am J Physiol Endocrinol Metab 2005; 289: E608–E616.
38 Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G,
Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats
derive directly from white adipocytes. Am J Physiol Cell Physiol
2000; 279: C670–C681.
39 Ghorbani M, Himms-Hagen J. 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 1997; 21: 465–475.
40 Kajimura S, Seale P, Spiegelman BM. Transcriptional control of
brown fat development. Cell Metab 2010; 11: 257–262.
41 Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B,
Nedergaard J. Chronic peroxisome proliferator-activated receptor
{gamma} (PPAR{gamma}) 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 2010; 285: 7153–7164.
42 Murano I, Barbatelli G, Giordano A, Cinti S. Noradrenergic
parenchymal nerve fiber branching after cold acclimatisation
correlates with brown adipocyte density in mouse adipose organ.
J Anat 2009; 214: 171–178.
43 Nedergaard J, Golozoubova V, Matthias A, Shabalina I, Ohba K,
Ohlson K et al. Life without UCP1: mitochondrial, cellular and
organismal characteristics of the UCP1-ablated mice. Biochem Soc
Trans 2001; 29: 756–763.
44 Bouillaud F. UCP2, not a physiologically relevant uncoupler but a
glucose sparing switch impacting ROS production and glucose
sensing. Biochim Biophys Acta 2009; 1787: 377–383.
45 Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H,
Harper ME et al. Mice lacking mitochondrial uncoupling protein
are cold-sensitive but not obese. Nature 1997; 387: 90–94.
46 Nedergaard J, Cannon B. The ‘novel’ ‘uncoupling’ proteins UCP2
and UCP3: what do they really do? Pros and cons for suggested
functions. Exp Physiol 2003; 88: 65–84.
47 Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat.
Physiol Rev 1984; 64: 1–64.
48 Gonzalez-Barosso MMR E. The role of fatty acids in the activity of
the uncoupling protein. Curr Chem Biol 2009; 3: 180–188.
49 Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F. Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep
2005; 25: 227–249.
50 Collins S, Cao W, Robidoux J. Learning new tricks from old dogs:
beta-adrenergic receptors teach new lessons on firing up adipose
tissue metabolism. Mol Endocrinol 2004; 18: 2123–2131.
51 Rim JS, Kozak LP. Regulatory motifs for CREB-binding protein
and Nfe2l2 transcription factors in the upstream enhancer of the
mitochondrial uncoupling protein 1 gene. J Biol Chem 2002; 277:
34589–34600.
52 Watanabe M, Yamamoto T, Mori C, Okada N, Yamazaki N,
Kajimoto K et al. Cold-induced changes in gene expression in
brown adipose tissue: implications for the activation of thermogenesis. Biol Pharm Bull 2008; 31: 775–784.
53 Debevec D, Christian M, Morganstein D, Seth A, Herzog B, Parker
M et al. Receptor interacting protein 140 regulates expression of
uncoupling protein 1 in adipocytes through specific peroxisome
proliferator activated receptor isoforms and estrogen-related
receptor alpha. Mol Endocrinol 2007; 21: 1581–1592.
54 Bargmann W, von Hehn G, Lindner E. On the cells of the brown
fatty tissue and their innervation]. Z Zellforsch Mikrosk Anat 1968;
85: 601–613.
55 Bartness TJ, Song CK. Innervation of brown adipose tissue and its
role in thermogenesis. Can J Diabetes 2005; 29: 420–428.
56 Landsberg L, Saville ME, Young JB. Sympathoadrenal system and
regulation of thermogenesis. Am J Physiol 1984; 247: E181–E189.
57 Bachman ES, Dhillon H, Zhang CY, Cinti S, Bianco AC, Kobilka
BK et al. BetaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 2002; 297: 843–845.
International Journal of Obesity
Brown adipocyte development and thermogenesis
D Richard et al
S66
58 Lowell BB, Bachman ES. Beta-adrenergic receptors, diet-induced
thermogenesis, and obesity. J Biol Chem 2003; 278: 29385–29388.
59 Jimenez M, Leger B, Canola K, Lehr L, Arboit P, Seydoux J et al.
Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese
and cold-sensitive but have normal lipolytic responses to fasting.
FEBS Lett 2002; 530: 37–40.
60 Richard D. Energy expenditure: a critical determinant of energy
balance with key hypothalamic controls. Minerva Endocrinol 2007;
32: 173–183.
61 Berthoud HR, Morrison C. The brain, appetite, and obesity. Annu
Rev Psychol 2008; 59: 55–92.
62 Grill HJ. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring)
2006; 14 (Suppl 5): 216S–221S.
63 Cone RD. Studies on the physiological functions of the
melanocortin system. Endocr Rev 2006; 27: 736–749.
64 Ellacott KL, Cone RD. The role of the central melanocortin
system in the regulation of food intake and energy homeostasis:
lessons from mouse models. Philos Trans R Soc Lond B Biol Sci
2006; 361: 1265–1274.
65 Adan RA, Tiesjema B, Hillebrand JJ, la Fleur SE, Kas MJ, de Krom
M. The MC4 receptor and control of appetite. Br J Pharmacol
2006; 149: 815–827.
66 Butler AA. The melanocortin system and energy balance. Peptides
2006; 27: 281–290.
67 Ste Marie L, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD. A
metabolic defect promotes obesity in mice lacking melanocortin4 receptors. Proc Natl Acad Sci USA 2000; 97: 12339–12344.
68 Glavas MM, Joachim SE, Draper SJ, Smith MS, Grove KL.
Melanocortinergic activation by melanotan II inhibits feeding
and increases uncoupling protein 1 messenger ribonucleic acid in
the developing rat. Endocrinology 2007; 148: 3279–3287.
69 Brito MN, Brito NA, Baro DJ, Song CK, Bartness TJ. Differential
activation of the sympathetic innervation of adipose tissues by
melanocortin receptor stimulation. Endocrinology 2007; 148:
5339–5347.
70 Song CK, Jackson RM, Harris RB, Richard D, Bartness TJ.
Melanocortin-4 receptor mRNA is expressed in sympathetic
nervous system outflow neurons to white adipose tissue. Am J
Physiol Regul Integr Comp Physiol 2005; 289: R1467–R1476.
71 Voss-Andreae A, Murphy JG, Ellacott KL, Stuart RC, Nillni EA,
Cone RD et al. Role of the central melanocortin circuitry in
adaptive thermogenesis of brown adipose tissue. Endocrinology
2007; 148: 1550–1560.
72 Harrold JA, Williams G. Melanocortin-4 receptors, beta-MSH and
leptin: key elements in the satiety pathway. Peptides 2006; 27:
365–371.
73 Oswal A, Yeo GS. The leptin melanocortin pathway and the
control of body weight: lessons from human and murine
genetics. Obes Rev 2007; 8: 293–306.
74 Ilnytska O, Argyropoulos G. The role of the Agouti-Related
Protein in energy balance regulation. Cell Mol Life Sci 2008; 65:
2721–2731.
75 Zhang Y, Kilroy GE, Henagan TM, Prpic-Uhing V, Richards WG,
Bannon AW et al. Targeted deletion of melanocortin receptor
subtypes 3 and 4, but not CART, alters nutrient partitioning and
compromises behavioral and metabolic responses to leptin.
FASEB J 2005; 19: 1482–1491.
76 Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB.
Identifying hypothalamic pathways controlling food intake,
International Journal of Obesity
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
body weight, and glucose homeostasis. J Comp Neurol 2005;
493: 63–71.
Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM,
McKinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose
tissue in the rat. Neuroscience 2002; 110: 515–526.
Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR
et al. Leptin activates hypothalamic CART neurons projecting to
the spinal cord. Neuron 1998; 21: 1375–1385.
Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB,
Elmquist JK. Expression of melanocortin 4 receptor mRNA in
the central nervous system of the rat. J Comp Neurol 2003; 457:
213–235.
Madden CJ, Morrison SF. Endogenous activation of spinal
5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue. Am J Physiol
Regul Integr Comp Physiol 2010; 298: R776–R783.
Nogueira MI, de Rezende BD, do Vale LE, Bittencourt JC. Afferent
connections of the caudal raphe pallidus nucleus in rats: a study
using the fluorescent retrograde tracers fluorogold and true-blue.
Ann Anat 2000; 182: 35–45.
Fan W, Morrison SF, Cao WH, Yu P. Thermogenesis activated by
central melanocortin signaling is dependent on neurons in the
rostral raphe pallidus (rRPa) area. Brain Res 2007; 1179: 61–69.
Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL.
Interactions between the melanocortin system and leptin
in control of sympathetic nerve traffic. Hypertension 1999; 33:
542–547.
Harthoorn LF. Projection-dependent differentiation of melaninconcentrating hormone-containing neurons. Cell Mol Neurobiol
2007; 27: 49–55.
Llewellyn-Smith IJ, Martin CL, Marcus JN, Yanagisawa M,
Minson JB, Scammell TE. Orexin-immunoreactive inputs to
rat sympathetic preganglionic neurons. Neurosci Lett 2003; 351:
115–119.
Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for
active brown adipose tissue in adult humans. Am J Physiol
Endocrinol Metab 2007; 293: E444–E452.
Enerback S. Human brown adipose tissue. Cell Metab 2010; 11:
248–252.
Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K,
Yoneshiro T, Nio-Kobayashi J et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects
of cold exposure and adiposity. Diabetes 2009; 58: 1526–1531.
Garcia CA, Van Nostrand D, Atkins F, Acio E, Butler C, Esposito G
et al. Reduction of brown fat 2-deoxy-2-[F-18]fluoro-D-glucose
uptake by controlling environmental temperature prior to
positron emission tomography scan. Mol Imaging Biol 2006; 8:
24–29.
Kim S, Krynyckyi BR, Machac J, Kim CK. Temporal relation
between temperature change and FDG uptake in brown adipose
tissue. Eur J Nucl Med Mol Imaging 2008; 35: 984–989.
Nedergaard J, Cannon B. The changed metabolic world with
human brown adipose tissue: therapeutic visions. Cell Metab
2010; 11: 268–272.
Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L,
Turcotte E, Carpentier AC et al. Outdoor temperature, age, sex,
body mass index, and diabetic status determine the prevalence,
mass and glucose-uptake activity of 18F-FDG-detected BAT. J Clin
Endocrinol Metab 2011; e-pub ahead of print 13 October 2010;
doi:10.1210/jc.2010-0989.