The brown adipocyte: Update on its metabolic role

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DOI: 10.1016/j.biocel.2004.04.003 · Source: PubMed
Abstract
Brown adipocytes are multilocular lipid storage cells that play a crucial role in non-shivering thermogenesis. These cells are located in brown adipose tissue (BAT) depots which are found in abundance in small mammals as well as in newborns of larger mammals, including humans. Brown adipocytes comprise a very large number of mitochondria packed with cristae and are densely innervated by the sympathetic nervous system (SNS). Sympathetic nerve endings release noradrenaline (NA) in the proximity of brown fat cells, where noradrenaline activates G-protein-coupled beta-adrenergic receptors (AR) and by doing so initiates a cascade of metabolic events culminating in the activation of uncoupling protein 1 (UCP1). Uncoupling protein 1 is a unique feature of brown adipocytes that allows for the generation of heat upon sympathetic nervous system stimulation. It is found in the inner membrane of the mitochondrion, where uncoupling protein 1 uncouples the oxidation of fuel from adenosine triphosphate (ATP) production. The expression of uncoupling protein 1 is strongly induced by cold exposure, revealing the importance of this uncoupling protein in thermoregulation. The thermoregulatory role of uncoupling protein 1 has been emphasized in uncoupling protein 1-deficient mice, whose resistance to cold is impaired. Uncoupling protein 1 expression is modulated by diet and metabolic hormones such as leptin and glucocorticoids, which suggests that the protein is a player in energy balance regulation.
The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104
Cells in focus
The brown adipocyte: update on its metabolic role
Henrike Sell, Yves Deshaies, Denis Richard
Department of Anatomy and Physiology, School of Medicine, Laval Hospital Research Center and D. B. Brown Obesity Research Chair,
Laval University, Pavillon Ferdinand-Vandry, Local 3217, Quebec City, Que., Canada G1K 7P4,
Received 31 October 2003; received in revised form 30 March 2004; accepted 14 April 2004
Abstract
Brown adipocytes are multilocular lipid storage cells that play a crucial role in non-shivering thermogenesis. These cells
are located in brown adipose tissue (BAT) depots which are found in abundance in small mammals as well as in newborns
of larger mammals, including humans. Brown adipocytes comprise a very large number of mitochondria packed with cristae
and are densely innervated by the sympathetic nervous system (SNS). Sympathetic nerve endings release noradrenaline (NA)
in the proximity of brown fat cells, where noradrenaline activates G-protein-coupled
-adrenergic receptors (AR) and by
doing so initiates a cascade of metabolic events culminating in the activation of uncoupling protein 1 (UCP1). Uncoupling
protein 1 is a unique feature of brown adipocytes that allows for the generation of heat upon sympathetic nervous system
stimulation. It is found in the inner membrane of the mitochondrion, where uncoupling protein 1 uncouples the oxidation
of fuel from adenosine triphosphate (ATP) production. The expression of uncoupling protein 1 is strongly induced by cold
exposure, revealing the importance of this uncoupling protein in thermoregulation. The thermoregulatory role of uncoupling
protein 1 has been emphasized in uncoupling protein 1-deficient mice, whose resistance to cold is impaired. Uncoupling
protein 1 expression is modulated by diet and metabolic hormones such as leptin and glucocorticoids, which suggests that the
protein is a player in energy balance regulation.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: UCP1; Thermogenesis; Obesity; Energy balance
Cell facts
brown adipocytes are multilocular lipid storage cells comprising a large number of mitochondria packed with cristae;
brown adipocytes, which are unique to mammals, are densely innervated by sympathetic nervous system (SNS) nerve
endings, which release noradrenaline (NA) to stimulate brown adipocytes and uncoupling protein 1 (UCP1);
UCP1 is a unique feature of brown adipocytes and allows for the generation of heat;
UCP1isfoundintheinnermembraneofthemitochondrion,whereituncouplesfueloxidationfromadenosinetriphosphate
(ATP) production;
brown adipocytes are involved in non-shivering thermogenesis and UCP1 is accordingly induced or repressed by factors
such as cold, diet, leptin, corticosterone and obesity, which modulate thermogenesis.
Corresponding author. Tel.: +1-418-656-3348/+1-418-656-3347 (sec. office); fax: +1-418-656-7898.
E-mail address: denis.richard@phs.ulaval.ca (D. Richard).
1357-2725/$ see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biocel.2004.04.003
H. Sell et al./The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104 2099
1. Introduction
Brown adipocytes (Cannon & Nedergaard, 2004)
are grouped in brown adipose tissue (BAT) depots,
which are particularly visible in the interscapular, sub-
scapular, axillary, intercostal, perirenal, and periaortic
regions in small mammals as well as in human and
other larger mammalian newborns. In large mammals,
brown adipocytes become however rapidly unilocular
after birth and lose their ability to produce heat. In
mice, brown adipocytes can also be found in white adi-
pose tissue (WAT) depots upon differentiation of silent
brown adipocytes or transdifferentiation of existing
Fig. 1. Brown adipocyte histology and UCP1 function. (A) Morphological comparison of white and brown adipocytes. (B) Photomicrograph
of mouse BAT. Nu—nucleus, L—lipid droplets, Nv—nerve fiber. (C) Electron micrograph of a brown adipocyte with abundant mitochondria
that are labeled for UCP1. Arrows point to UCP1 labeling (immunogold, 14 nm). (Photomicrograph for (A) kindly provided by Dr. L.
Bukowiecki.)
adipocytes (Himms-Hagen et al., 2000). Ultrastruc-
turally (Fig. 1), brown adipocytes are characterized by
their high content of large mitochondria packed with
cristae that contain uncoupling protein 1 (Fig. 1C).
UCP1, the most critical feature to differentiate brown
from white adipocytes, is located in the inner mem-
brane of the mitochondrion where it uncouples the
electron transport through the respiratory chain from
adenosine triphosphate production (Nicholls & Locke,
1984). Brown adipocyte uncoupling is triggered by the
activation of the sympathetic nervous system, which
abundantlyinnervates BAT. SNS nerveendingsin BAT
release noradrenaline, which activates -adrenergicre-
2100 H. Sell et al. /The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104
ceptors (AR) and a cascade of events leading to BAT
cell proliferation, mitochondriogenesis, increased ex-
pression of UCP1 and UCP1 activation.
2. Cell origin, differentiation, and plasticity
In most species, brown adipocytes develop dur-
ing the fetal stage or shortly after birth (Cannon
& Nedergaard, 2004). Brown adipocyte precursor
cells have been shown in vivo to mature sequen-
tially into protoadipocytes, preadipocytes, and brown
adipocytes (Geloen, Collet, Guay, & Bukowiecki,
1990). The latter are characterized by multilocular
triglyceride droplets and the presence of abundant
and large mitochondria packed with cristae that con-
tain UCP1 protein (Fig. 1B and C). In rodents, brown
adipocytes mature rapidly during the first days after
birth while at birth only small amounts of BAT are
present (Cannon & Nedergaard, 2004). UCP1 ex-
pression appears shortly before birth and continues
to increase afterwards. In humans, brown adipocytes
are present in embryos beginning at the 20th week
of pregnancy and BAT reaches 1% of body weight
at birth (Lean & James, 1986). However, soon after
birth human brown adipocytes increasingly accumu-
late lipids, become devoid of mitochondria and more
or less lose their thermogenic capacity. In adult ro-
dents, brown adipocytes may be present in white fat
depots, where they differentiate from precursors in re-
sponse to certain stimuli. Brown adipocytes in white
adipose tissue may also result from direct conversion
of white to brown adipocytes (Himms-Hagen et al.,
2000). Proliferation and differentiation of BAT is
stimulated by the SNS. Brown adipocyte precursors
express
1
-adrenergic receptors that are crucial for
proliferation whereas the
3
-AR stimulates differen-
tiation (Cannon & Nedergaard, 2004). Mature brown
adipocytes mainly express
1
- and
3
-AR.
3. Functions and regulation
Research in the 1970’s has established that BAT mi-
tochondria exhibit abnormal ion conductivity, which
led to the view that a mitochondrial membrane protein
is responsible for this characteristic behavior. The exis-
tence in BAT mitochondrion of an uncoupling protein
(UCP—also called thermogenin), which was specif-
ically induced during cold adaptation, was demon-
strated in 1976 (Ricquier & Kader, 1976). This protein
was characterized in 1983 (Ricquier, Thibault, Bouil-
laud & Kuster, 1983) following its isolation (Lin &
Klingenberg, 1980). Since the unveiling of new UCPs,
UCP/thermogenin has been referred to as UCP1. The
‘novel’ UCPs, namely UCP2 and UCP3, are proteins
homologous to UCP1 that, despite what was first pos-
tulated, cannot be considered as being thermogenic
(Nedergaardet al., 2001) even though theyare found in
brown adipocytes. UCP2 is expressed throughout the
body and is believed to repress the generation of reac-
tive oxygen species (Arsenijevic et al., 2000). UCP3
is highly expressed in muscle, where its expression
is regulated by fasting and exercise (Russell et al.,
2003).
UCP1, the archetypal UCP, is uniquely expressed
in brown adipocytes where it generates heat by un-
coupling substrate oxidation and electron transport
through the respiratory chain from adenosine-5
-
triphosphate (ATP) synthesis (Klingenberg & Huang,
1999). The uncoupling process is demonstrated in
Fig. 2A. As illustrated, mitochondrial oxidation of
fatty acids generates the electron donors, nicotinamide
adenine dinucleotide (NADH) and flavin adenine
dinucleotide (FADH
2
). NADH- and FADH
2
-derived
electrons move down the respiratory chain, associ-
ated with pumping of protons from the mitochondrial
matrix into the intermembrane space. This creates
across the inner mitochondrial membrane an elec-
trochemical proton gradient (µH
+
), which gen-
erates the proton motive force being used in most
tissues to drive conversion of ADP to ATP by ATP
synthase. In brown adipocytes, UCP1 provides an
alternative way for protons to reenter the mitochon-
drial matrix, thereby uncoupling the oxidation of fuel
from ATP synthesis. In brown adipocytes, substrate
oxidation occurs at an accelerated rate due to the
absence of the constraint of ATP generation. UCP1
increases proton leakage across the inner membrane
of brown adipocyte mitochondria and thereby dissi-
pates the proton motive force as heat instead of ATP
synthesis.
UCP1-mediated thermogenesis in BAT is under
SNS control, whose activity is governed by selective
hypothalamic regions. Recent experiments using vi-
ral tract tracers have substantiated the existence of
H. Sell et al./The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104 2101
Fig. 2. (A) UCP1 is located in the mitochondrial inner membrane where it uncouples substrate oxidation from ATP synthesis, thereby
dissipating energy as heat. (B) Energy expenditure through thermogenesis in BAT is regulated by the SNS through NA release. Increased
sympathetic stimulation leads to
3
-AR activation, increased cAMP generation and activation of PKA. Furthermore, LPL is stimulated
to increase fatty acid uptake by the cell. PKA activation has acute effects on lipolysis and therefore increases substrate availability for
thermogenesis. The chronic effects of PKA activation include mitochondrial biogenesis, brown adipocyte differentiation and increased
UCP1 expression.
anatomical and functional links between BAT and hy-
pothalamic neurons of the melanocortinergic system
(Bartness, T. and Richard, D., unpublished results).
SNS nerve endings reach individual brown adipocytes
and release NA, which stimulates BAT thermogenic
activity by binding to - and -adrenergic receptors.
Brown adipocytes express various adrenergic recep-
tors that include the
1
- and
3
- receptors, and it has
become clear over the years that the
3
-AR is, at least
in rodents, the most prominent AR in driving the cas-
cade of events necessary for heat production in BAT
(Fig. 2B). Adrenergic receptors are members of the
2102 H. Sell et al. /The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104
family of G-protein-coupled receptors. When stim-
ulated these receptors trigger a series of metabolic
events leading to the activation of hormone sensitive
lipase (HSL), a rate-limiting step in lipolysis. HSL
liberates free fatty acids (FFA) from intracellular
lipid stores. FFA are then transformed into acyl-CoA
and transported into mitochondria as acyl-carnitine.
Finally, -oxidation of acyl-CoA inside the mito-
chondria drives the electron transport chain and the
generation of the proton gradient at the mitochondrial
inner membrane. In the process of thermogenesis,
FFA act not solely as substrates for -oxidation and
subsequent electron transport through the respiratory
chain, but are also involved in the uncoupling process.
The SNS also controls (i) BAT cell proliferation
through
1
- adrenergic receptor-mediated processes,
(ii) mitochondriogenesis, and (iii) the expression of
UCP1 via a protein kinase A-mediated activation of
its cAMP response element (CRE). UCP1 expression
is also regulated by different nuclear receptors and co-
factors such as peroxisome proliferator-activated re-
ceptor (PPAR) and PPAR coactivator 1 (PGC1),
and it possesses a PPAR response element (PPRE). In
fact, PPAR agonists such as the anti-diabetic thiazo-
lidinediones rosiglitazone and troglitazone have been
recently found to noticeably increase UCP1 expres-
sion in brown adipocytes (Digby et al., 1998) (Sell,
H., Deshaies, Y. and Richard, D., unpublished results).
Very recently, it has also been demonstrated that trans-
fection of PGC1 into white adipocytes can generate
several cellular actions of brown adipocytes such as
increased expression of UCP1 and proteins involved in
fatty acid oxidation and the respiratory chain (Tiraby
et al., 2003).
BAT SNS activity is stimulated or inhibited in
different physiological situations. Cold exposure and
palatable/high energy density diets are known to ac-
tivate the SNS, whereas fasting has been reported
to exert the opposite effect. BAT thermogenesis and
UCP1 expression are increased during chronic cold
exposure to produce heat, and during high-fat feed-
ing, possibly to regulate body weight (Rothwell &
Stock, 1983). In fasted animals, energy expenditure
through thermogenesis and UCP1 expression are de-
creased. In humans, there is some evidence that BAT
still preserves some thermogenic activity in adults
as cervical BAT and mitochondrial oxidative activity
increase in outdoors workers (Huttunen, Hirvonen &
Kinnula, 1981). Thermogenesis and UCP1 expres-
sion are also regulated by agonists of the
3
-AR and
PPAR, as well as by various hormones including lep-
tin, thyroid hormones and glucocorticoids. Leptin, an
adipocyte-derived factor, is one of the key regulators
of adiposity and acts centrally to decrease food intake
and increase thermogenesis (Commins et al., 1999),
thereby orchestrating metabolic changes leading to
loss of adipose tissue. Glucocorticoids are among
the strongest down-regulators of UCP1 expression
in BAT (Arvaniti, Ricquier, Champigny, & Richard,
1998).
4. Associated pathologies
Revealing insights into the physiological impor-
tance of BAT come from various animal models
with brown adipocyte ablation, UCP1 overexpres-
sion, or knockout of -adrenergic receptors. Trans-
genic mice with ablation of BAT induced by brown
adipocyte-specific expression of diphtheria toxin A
chain controlled by the UCP promoter (UCP-DTA
mice) become obese and hyperphagic (Kozak &
Harper, 2000). In this model, decreased BAT activ-
ity is not only associated with obesity but also with
insulin resistance and hyperlipidemia. On the other
hand, mice overexpressing UCP1 are resistant to obe-
sity. In addition, mice that lack all three -adrenergic
receptors have a reduced metabolic rate and are
severely obese when fed a high energy diet (Bachman
et al., 2002). In humans, combined polymorphisms in
UCP1 and the
3
-AR are known to be associated with
obesity and possibly with type 2 diabetes. Synergistic
effects of
3
-AR and UCP1 polymorphisms include a
higher risk for weight gain and a significantly lower
basal metabolic rate (Valve et al., 1998), suggesting
a link between energy balance, BAT and obesity in
humans. As for rodents, obese ob/ob mice (Commins
et al., 1999) and Zucker fa/fa rats display significantly
lower levels of UCP1 protein and higher lipid accu-
mulation, a sign of decreased thermogenesis in BAT.
It is worthy of mention that not all data emerging
from studies carried out in genetically-engineered an-
imal models convey the message that UCP1 and BAT
are key to energy balance regulation. UCP1 knockout
mice are not prone to obesity but only cold sensi-
tive, suggesting that UCP1 does not play an essential
H. Sell et al./The International Journal of Biochemistry & Cell Biology 36 (2004) 2098–2104 2103
role in obesity (Enerback et al., 1997). Indeed, UCP1
knockout mice are resistant to diet-induced thermo-
genesis, a paradox that argues against a role of UCP1
in this form of thermogenesis. In the same line, UCP1
polymorphisms alone seem not to be clearly associ-
ated with obesity in humans (Hamann et al., 1998).
Despite the evidence for a role of BAT and UCP1 in
the control of thermogenesis in rodents, one has to be
cautious regarding the role of BAT and UCP1 in adult
humans as a potential target for anti-obesity drugs.
BAT is barely present in human adults, and despite
15 years of intensive labor to develop
3
-AR agonists
to treat obesity, there are still no valid strategies to
induce BAT recruitment or to increase UCP1 activity
that, in humans, translate into significant anti-obesity
effects. However, it has become clear over the years
that thermogenesis is not a trivial determinant in
energy balance regulation in humans, and the de-
velopment of anti-obesity drugs aimed at increasing
energy expenditure remains a significant therapeutic
objective. Experimental work aimed at understanding
the physiological role of BAT thermogenesis has been
largely instrumental in underlying the importance of
considering energy expenditure in the treatment of
obesity.
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    • "Stimulation of β3AR induces increased cyclic AMP (cAMP) generation and subsequent activation of protein kinase A (PKA). Hormone-sensitive lipase (HSL), p38 α-mitogen-activated protein kinase (p38αMAPK), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) are downstream molecules of PKA [15, 24]. Activating transcription factor 2 (ATF2) and cAMP response element binding protein (CREB) bind to the PGC1α promoter and enhance its transcription [25]. "
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    Full-text · Article · Dec 2015
    • "Thus, decreased lipid oxidation seems not to be the mechanism of obesity in these mice. Impaired thermogenic function of BAT is a commonly detected mechanism of obesity in mouse models, also in NPY-induced obesities (Arbeeny et al., 1995; Chao et al., 2011; Sell et al., 2004; Shi et al., 2013). Increased lipid content of BAT and decreased mRNA expression of thermogenesis marker uncoupling protein-1 (Ucp1) imply that this is the case also in homozygous OE-NPY DβH mice (Vähätalo et al., 2015b). "
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    • "In both tissues uncoupling proteins (UCP), localized at the inner mitochondrial membrane, are responsible for heat dissipation. UCP1 is the most prominent protein of this family and is limited to BAT (Sell et al., 2004). UCP1 is primarily activated by noradrenergic stimulation mediated by the SNS, but T3 is involved as coactivator and is essential for the full thermogenic response of BAT (Bianco and Silva, 1987; Silva and Larsen, 1986). "
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