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Biochemical Society Transactions (200 I ) Volume 29, part 6
Uncoupling protein 2 in the brain: distribution and function
D. Richard', S. Clavel, Q. Huang. D. Sanchis and D. Ricquier
Centre de recherche de I'h6pital Laval et Centre de recherche sur le metabolisme energetique de I'Univenite
Laval, Faculte de medecine, Univenite Laval, Quebec, Canada G I K 7P4
Abstract
determine the exact function of UCP2, it nonetheless suggests that UCP2 can fulfil more general
functions than U C P l and UCP3. T h e role of
UCP2 has yet to be fully delineated, even though
two recent studies carried out in UCP2-- mice
have suggested that this protein could be involved
in the production of reactive oxygen species (ROS)
[2], as well as in the control of insulin secretion [3].
In contrast with what was first anticipated, UCP2
does not seem to be a major effector of thermoregulatory processes, but the possibility that
this protein can be involved in obesity remains
factual [4].
Another characteristic feature of UCP2 is
that it is expressed in the brain [l], where the
distribution of UCP2 mRNA is wide, but specific
to certain areas [S]. T h e focus of this mini-review
is to discuss the potential functions of UCPZ in the
brain in the light of its distribution, uncoupling
activity and role in the control of ROS production.
Uncoupling protein 2 (UCP2) mRNA is expressed
in a panoply of tissues, including the brain, where
it is widely distributed. In the mouse brain, it is
expressed in the hypothalamus (suprachiasmatic,
paraventricular, dorsomedial, ventromedial and
arcuate nuclei), the thalamus (submedius nucleus)
and the brain-stem (dorsal motor nucleus of the
vagus nerve). In the rat brain, it is also expressed
in the hippocampus. T h e presence of UCP2
mRNA in neurons expressing corticotropin-releasing factor and arginine-vasopressin suggests a
role for UCP2 in the control of neuroendocrine
and behavioural functions. We have recently
demonstrated that UCP2-deficient mice can resist
the lethal effect of toxoplasmosis through an
enhanced production of reactive oxygen species
(ROS) from the macrophages. This finding provides evidence that UCPZ can be part of a
mechanism preventing ROS production. UCP2
could therefore be involved in protecting the brain
against oxidative stress. T h e involvement of UCP2
in neuroprotection is also consistent with the
recent observation that kainic acid, which promotes Ca2+uptake in the glutamate-activated neurons in the hippocampal CAI field, can induce the
UCPZ gene in the activated CAI cells. T h e role
of UCP2 in neuroprotection warrants further
investigation.
Uncoupling proteins
Mainly on the basis of studies addressing the
function of U C P l [6], UCPs have been described
as mitochondrial inner membrane proteins capable of dissipating the proton electrochemical
gradient (ApH') that builds up across the inner
mitochondrial membrane and drives the A T P
synthase pathway (Figure 1) [6]. This uncoupling
process is susceptible to decreases in A T P synthesis and generation of significant amounts of
heat, as is the case of BAT, which serves as
an efficient thermogenic effector in small mammals [7].
UCPs have also been demonstrated to be
involved in ROS production [2], which seems to
be facilitated in totally coupled mitochondria [8,9].
In fact, the increase in ApH+, which occurs when
a mitochondrion is in respiration state 4 (that is,
when A T P levels are high and the availability of
A D P is low), would slow down the electron flow
through the respiratory chain. This would facilitate the transfer of electrons from ubisemiquinone radicals to 0, and subsequently promote the
formation of superoxide radicals (02.-).
T h e total
coupling of mitochondria could also enhance the
Introduction
Uncoupling protein 2 (UCP2) is a member of the
mitochondrial carrier superfamily with a predicted
homology of sequence of 59", with UCPl [l]. In
contrast with the other UCPs, such as UCP1,
which is uniquely expressed in brown adipose
tissue (BAT), or UCP3, which is found in B A T
and muscle, UCPZ is expressed in a large number
of tissues. Although this specificity does not
Key words: mitochondrion, neuroendocnnology. neuroprotection. rat
Abbreviations used: UCP2. uncoupling protein 2 : ROS. reactive
oxygen species: BAT. brown adipose tissue: CRF. corticotropinreleasing factor: AVP. arginine-vasopressin.
'To whom correspondence should be addressed (e-mail
denis.richard(u8phs.ulaval.ca).
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812
Mitochondria1Uncoupling Proteins
Schematic showing the bioenergetical function of UCPZ
The potential function of uncoupling protein 2 (UCP2). similar t o the other UCPs, is t o dissipate
the proton electrochemical gradient (ApH') that builds up across the inner mitochondrial
membrane and drives the ATP-synthase pathway. This uncoupling process is susceptible to the
reducing of ATP synthesis and the prevention of the transfer of electrons from ubisemiquinone
radicals t o 0, and, subsequently,the formation of reactive oxygen species, such as superoxide
radicals (02'-).
mitoehoodrial
outer
membrane
%ll
mitochondrial
inner
membrpm
mitochondrial matrix
1
mRNA is found in large amounts in the hypothalamus, the limbic system and in the brainstem.
In the rat, as well as in the mouse [S], the
hypothalamic expression of UCP2 is abundant
in the suprachiasmatic, paraventricular, dorsomedial, ventromedial nucleus and arcuate nuclei.
In both species, the expression of UCP2 is marked
in the dorsal motor nucleus of the vagus nerve. In
the mouse, UCP2 mRNA is abundantly expressed
in the cerebellum, but hardly so in the hippocampus. T h e cerebellar expression is not seen in
the rat, which, however, exhibits a strong expression of UCP2 in the hippocampus (Figure 2). T h e
reasons for differences between strains in the expression of UCP2 are still obscure.
There is now evidence that expression is
largely neuronal [5,20]. T h e chemical identity of
the neurons expressing UCP2 mRNA has yet to be
fully determined. Nonetheless, it is clear that
neurons expressing corticotropin-releasing factor
(CRF) in the parvocellular division of the paraventricular hypothalamic nucleus and arginine-
production of ROS by generating more NADPH
through the activation of nicotinamide-nucleotide
transhydrogenase [lo]. In the presence of a functional NADPH oxidase system, oxidation of
NADPH could produce 02'-,
even in cells other
than phagocytes [ 111.
U p until now, no less than three mammalian
UCPs, referred to as U C P I , UCP2 and UCP3,
have been cloned and identified as members of the
U C P subfamily [12-141. Other UCPs, cloned in
plants [15] and birds [16], are also part of this
family. Furthermore, two other mitochondrial
proteins with uncoupling activities have recently
been discovered, and designated UCP4 [17] and
BMCPl [18,19].
Brain distribution of UCPZ mRNA
One striking feature of the UCP2 gene is that it is
expressed to a significant level in the brain [S].
Studies conducted in the mouse, as well as in the
rat (Figure 2), have demonstrated that UCP2
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0 200 I Biochemical Society
Biochemical Society Transactions (200 I ) Volume 29. part 6
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The expression of UCPZ mRNA in the rat brain
The film autoradiograms represent coronal rat brain sections that were hybridized with an
antisense riboprobecomplementaryto the rat UCP2 mRNA. RegionsexpressingUCPZ mRNA
are emphasized. ' 10'. dorsal motor nucleus of the vagus nerve: AP, area postrrma: ARH.
arcuate hypothalamic nucleus: BLA. basolateral amygdaloid nucleus: CAI, Ammon's horn I field
of the hippocampus: CA3.Ammon's horn 3 field of the hippocampus: DMH. dormmedial
hypothalamic nucleus: LV, lateral ventncle: PVN. paraventricular hypothalamic nucleus: SCH.
suprachiasmatic nucleus: SON, supraoptic nucleus; VMH. ventromedial hypothalamic nucleus.
1 DMH
vasopressin in the magnocellular division of the
paraventricular and supraoptic nuclei (Figure 3)
expressed UCPZ mRNA. The UCPZ gene is not
constitutively expressed in astrocytes and nonactivated microglial cells.
0 200 I Biochemical Society
Brain distribution and function of
UCp2 in the brain
T h e brain distribution, as well as the cellular
localization, of UCP2 mRNA in the brain supports
814
Mitochondria1Uncoupling Proteins
Neurons expressing CRF in the paraventricular hypothalamic nucleus (PVN) and arginine-vasopressin in the supraoptic nucleus (SON)
express UCP2 mRNA. CRH and AVP neurons were first immunostainedand hybridized with an antisense riboprobe complementary to the
rat UCPZ mRNA. Doubly labelled cells are indicated by arrows. Magnification, x 20 (left panels) and x I00 (right panels). 3V, third ventricle.
this mutant has an increased ability to secrete
insulin [3], which suggests that UCPZ might play
some role in energy metabolism.
T h e expression of UCP2 mRNA in C R F
and AVP cells raises the possibility that UCP2
is involved in neuroendocrine functions. C R F is
expressed abundantly in the parvocellular division
of the paraventricular nucleus, from which C R F
neurons project to the median eminence to control
the activity of the pituitary-adrenal axis. It is
noteworthy that C R F neurons other than those
from the paraventricular nucleus do not express
UCP2 mRNA (D. Richard, unpublished results),
indicating that UCP2 could play a role in neuroendocrine neurons specifically. UCP2 is also
expressed in AVP neurons, whose role in the
control the hydric balance has been credited
for years. A role for UCP2 in neuroendocrine
secretions appears feasible in the light of the recent
demonstration of the involvement of UCP2 in
insulin secretion [3]. Because it has the ability to
control A T P levels, UCP2 has been assumed
to influence /?-cell glucose sensing. By controlling
a role for UCP2 in energy balance regulation,
neuroendocrine and autonomic functions.
In the hypothalamus, UCP2 mRNA is found
in at least four structures, playing a very important
role in the control of food intake and energy
expenditure. UCP2 mRNA is indeed expressed in
the paraventricular, dorsomedial, ventromedial
and arcuate nuclei [21]. In the arcuate nuclei,
UCP2 mRNA has been found in neurons containing neuropeptide Y and agouti-related protein
(A. Dunn-Meynel, B. Levin and D. Richard,
unpublished results), which are undeniably two of
the most important neuropeptides involved in the
regulation of energy balance in laboratory rodents
[22]. T h e putative role of UCP2 in the control of
food intake and thermogenesis needs, however, to
be ascertained. Factors such as obesity, leptin
treatment and food deprivation do not apparently
alter the expression of UCP2 in the brain (D.
Richard, unpublished results). In addition, the
UCP2-- mouse does not appear to exhibit major
changes in terms of energy balance regulation [2].
However, it has been demonstrated recently that
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Biochemical Society Transactions (200 I ) Volume 29. part 6
A T P levels, UCP2 could also modulate the activity
of the C R F and AVP neurons; the use of inhibitors of A T P synthesis has been reported to lower
significantly the rates of basal and potassiuminduced C R F release in a hypothalamic superfusion system [23].
One of the brain nuclei that express the most
UCP2 is the dorsal motor nucleus of the vagus
nerve, suggesting a role for UCPZ in the activity of
the parasympathetic nervous system. In addition, the UCP2 transcript is found in the nucleus
of the solitary tract and the area postrema. These
two nuclei, together with the dorsal motor nucleus
of the vagus nerve, form the dorsal vagal complex,
a role for which in the integrated visceral functions
appears irrefutable [24].
glutamate, a cellular Ca2+overload is capable of
initiating either necrotic or apoptotic pathways
leading to cell death. UCP2, by lowering the mitochondrial ApH’, could limit the Ca2+-buffering
capacity of the mitochondrion in order to protect cells against the detrimental effect of an
overload of Ca”. That UCPZ can be involved in
protecting cells overloaded by Ca2+is consistent
with the recently observed increase in UCP2 expression in the CA (Ammon’s horn)-1 field of the
hippocampus in mice subjected to an acute intraperitoneal injection of kainic acid (S. Clavel and
D. Richard, unpublished work). T h e CA1 field,
which does not constitutively express UCP2
mRNA in the mouse, undergoes a strong activation following treatment with kainic acid [26].
UCPZ and neuroprotection
Conclusion
Given the apparent importance of UCP2 in the
control of ROS production [2,9], it seems reasonable to hypothesize that UCP2 is part of a system
limiting the neurodegerative processes associated
with oxidative stress. Even though the deficiency
in UCP2 mRNA has been reported to have
beneficial effect in the resistance to infection by
promoting macrophagic microbiocidal activity [2],
the fact remains that ROS production, when it is
sustained, has detrimental effects on cells. T h e
marked expression of UCP2 in macrophages during infection probably occurs as a means to protect
surrounding cells against ROS. Not many studies
to date have addressed the role of UCPZ in
neurodegenerative processes attibutable to oxidative stress, but it seems clear that brain injuries
cause the infiltration of phagocytic cells abundantly expressing UCP2 (S. Clavel and D.
Richard, unpublished work). In the case of brain
injuries, microglial cells are also observed to
express UCPZ mRNA (S. Clavel, D. Arsenijevic
and D. Richard, unpublished work). As yet, it is
unclear as to whether UCP2 protects neurons that
constitutively express it.
In addition to protecting neurons by preventing the production of ROS, UCP2 could also
contribute to neuroprotection via at least one
supplementary mechanism, which is still speculative. T h e fact that UCP2 can reduce the mitochondrial ApH+ suggests that this protein could
participate in the Ca”-buffering capacity of the
mitochondria, which seems in large part mediated
by the mitochondrial ApH’ [25]. There is now a
consensus that mitochondria play a vital role in
buffering the cytosolic calcium overload in stimulated neurons. In mammalian neurons exposed to
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UCP2 is a unique UCP. It is expressed in an
impressive array of tissues, including the brain,
where the distribution of its mRNA is widespread,
although specific to certain nuclei. T h e brain
distribution and localization of UCP2 mRNA in
C R F and AVP neurons suggest a role for UCP2
in energy balance regulation, as well as in neuroendocrine and autonomic functions. A role of UCP2
in the neuroendocrine functions is supported by
the recent demonstration that UCP2 can be a
regulator of ATP-dependent hormonal secretions
[3]. Recent studies [2,9] have suggested that UCP2
can negatively control ROS production, raising
the possibility that brain UCP2 can protect neurons against oxidative stresses. A role for UCP2 in
neuroprotection is supported further by the recent
observation that kainic acid, which promotes Ca2+
uptake in the glutamate-activated neurons in the
hippocampus, can induce UCP2 expression in
the activated CAI cells. T h e protective role of
UCPs against excitotoxicity lends itself to an interesting avenue of research in the light of the
mitochondrial ApH+-dependent Ca’+-buffering
capacity of the mitochondrion [25].
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