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Department of Obstetrics and Gynecology (S.D., G.N., F.N., T.L.H.) and Section of Neurobiology (T.L.H.), Yale University School of Medicine, New Haven, Connecticut 06520; Division of Neuroscience (H.F.U.), Oregon Regional Primate Research Center, Beaverton, Oregon 97006; Department of Pediatric Anesthesiology and Intensive Care (B.H.), Aladar Petz County Hospital, Gyor 9023, Hungary; Department of Anatomy, Cell and Neurobiology (I.B.), Humboldt-University, Charite, Berlin 10098, Germany; Nursing, School of Allied Medical Sciences (A.K.), Hirosaki University, Hirosaki 036-8564, Japan; and Rowe Program in Human Genetics (C.H.W.), Department of Pediatrics and Section of Neurobiology, Physiology, and Behavior, School of Medicine, University of California at Davis, Davis, California 95616
Address all correspondence and requests for reprints to: Tamas L. Horvath/Sabrina Diano, Department Ob/Gyn, Yale University, School of Medicine, 333 Cedar Street FMB 339, New Haven, Connecticut 06520. E-mail: tamas.horvath@yale.edu or sabrina.diano{at}yale.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the process of storing energy, the hydrogen proton gradient that exists between the intermembrane space and mitochondrial matrix, serves to transform the positive energy in the high-energy compound ATP. In the mitochondria there are molecules located in the inner membrane that dissipate energy contained in the nutrients through the uncoupling of the respiratory chain from oxidative phosphorylation. When these molecules, called uncoupling proteins (UCPs), are present they may transform the positive energy from the hydrogen proton gradient into heat, thereby, diminishing energy storage.
To date, five putative uncoupling proteins (UCP1, UCP2, UCP3, UCP4, and brain mitochondrial carrier protein 1 [BMCP1]) have been discovered, and all of them can promote partial uncoupling of the mitochondrial proton gradient from ATP production in yeast and/or mammalian cells (3, 4, 5, 6, 7, 8, 9, 10). The five UCPs have different tissue distribution patterns and appear to be regulated differently, suggesting that they may have distinct physiological roles. While UCP1 and UCP3 are expressed only in the peripheral tissues (3, 4, 5, 7, 8), UCP2, UCP4 and BMCP1 are expressed in the central nervous system as well (6, 9, 11, 12). In the rodent brain, UCP2 is expressed predominantly in neuronal populations of subcortical regions that are involved in the central regulation of metabolic, endocrine, and autonomic processes (12), which is in contrast to the more ubiquitously distributed UCP4 and BMCP1 (9, 10). In particular, we (12) and others (11) have shown that the messenger RNA for UCP2 is localized in the supraoptic, paraventricular, suprachiasmatic, and arcuate nuclei of the hypothalamus of rodents. It has also been found that UCP2 protein is associated with the mitochondria and adjacent cytosol of neurons in the aforementioned regions and is coexpressed with several neuropeptides involved in metabolic, endocrine, and autonomic regulation, including neuropeptide Y (NPY), and with receptors for peripheral hormones such as leptin and gonadal steroids (12).
While data gathered on brain UCP2 in rodents suggest an important involvement of UCP2 in homeostatic regulation (12), Fleury et al. (6) failed to detect UCP2 expression in human brain samples. Consequently, it is unclear whether the rodent findings have any relevance to the physiology of humans or other mammals. To help clarify this issue, the present experiment used in situ hybridization histochemistry and immunocytochemisty to study the expression of UCP2 in the brains of nonhuman primates.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue preparation for in situ hybridization histochemistry
Rhesus macaque hypothalami and pituitary glands were
obtained from the Oregon Regional Primate Research Center (ORPRC)
Tissue Distribution Program. The animals were deeply anesthetized using
ketamine/pentobarbital according to procedures established by the Panel
on Euthanasia of the American Veterinary Society and perfused with 1
liter of 0.9% saline through the ascending aorta (at room temperature)
followed by 6.5 liter of ice-cold 4% paraformaldehyde in 0.1
M sodium phosphate buffer (pH 7.4). Hypothalami and
pituitary glands were then immersed in fresh fixative for an additional
3 h (at 4 C) and cryoprotected by immersion in 0.02 M
phosphate buffer (pH 7.4) containing glycerol (10% vol/vol) and
dimethyl sulfoxide (DMSO; 2% vol/vol) for 24 h, followed by
immersion in a more concentrated glycerol (20% vol/vol) phosphate/DMSO
solution for an additional 72 h. The tissues were then rapidly
frozen in 2-methyl butane (pre-cooled in an ethanol/dry-ice bath) and
stored at -85 C. Subsequently, they were sectioned (25 µm using a
freezing sliding microtome and mounted on glass microscope slides
(Fisherbrand Superfrost/Plus; Fisher Scientific, Auburn,
WA).
cRNA probe synthesis and in situ hybridization histochemistry
Human UCP2 riboprobe was used for the detection of UCP2 in
monkey hypothalamus. The amplification of the RNA sequence for UCP2 was
performed as previously described (6; 5' CATCTCCTGGGACGTAGC 3' and 5'
AGAGAAGGGAAGGAGGGAAG 3'). The resulting complementary DNA (1.1 kb),
purified from agarose gel using the QIA quick Gel Extraction Kit
(QIAGEN, Inc.), was digested with EcoRI and
inserted in pBluescript vector and then subcloned. Linearized DNAs by
HindIII and XbaI were transcribed using
T7 polymerase (antisense cRNA riboprobe) and
T3 polymerase (sense cRNA probe; restriction
enzyme XbaI; Riboprobe Combination System T3/T7, Promega Corp. Corporation, Madison, WI), respectively, and labeled with
35S-UTP(Amersham Pharmacia Biotech; 10
mCi/ml). The radiolabeled cRNA probe was then purified by passing the
transcription reaction solution over a G50 column (Amersham Pharmacia Biotech, Piscataway, NJ) and fractions were collected
and counted using a scintillation counter. In situ
hybridization (ISH) was performed on the tissue sections after first
bringing them to room temperature and postfixing them in 4%
paraformaldehyde in 0.1 M phosphate buffer (pH
7.4) for 15 min. The sections were then rinsed in phosphate buffer, and
digested with Proteinase K (10 µg/ml) in Tris-EDTA buffer (pH 8.0;
100 mM Tris, 50 mM EDTA)
for 30 min at 37 C. Next, they were acetylated, dehydrated with
ascending concentrations of ethanol, and dried under vacuum for 2
h. They were then hybridized for 18 h at 65 C with 100 µl of
35S-labeled antisense riboprobe, diluted to 1 x
107 cpm/ml of hybridization buffer (50
mM dithiothreitol, 250 µg/ml tRNA, 50%
formamide, 0.3 M sodium chloride, 1x Denhardt’s
solution, 20 mM Tris (pH 8.0), 1
mM EDTA, and 10% dextran sulfate). For the
hybridization, glass coverslips were affixed to the slides using DPX
mounting medium (BDH Laboratory Supplies, Poole, UK). They were
subsequently removed after two 30-min soakings in 4x saline-sodium
citrate buffer (SSC; the 20x stock solution comprised of 175.3 g
sodium chloride and 88.2 g sodium citrate per liter (pH 7.0))
containing 20 mM dithiothreitol (DTT). The
sections were then incubated in Tris-EDTA buffer (pH 8.0; 10
mM Tris, 1 mM EDTA, 0.5
M sodium chloride) containing RNase A (10
µg/ml) for 30 min at 37 C, followed by two 30-min washes at room
temperature with 2x SSC containing 1 mM DTT.
After a final 30-min wash at 70 C with 0.1x SSC containing 1
mM DTT, they were dehydrated through ascending
concentrations of ethanol, containing 0.3 M
ammonium acetate, and air-dried for 30 min. To visualize the
hybridization pattern, the sections were apposed to Hyperfilm ß-max
(Amersham Pharmacia Biotech) for 6 days.
As a control experiment, sections were incubated as described above with hybridization solution containing the sense-strand probe synthesized with T3 polymerase to transcribe the coding strand of the DNA insert.
Tissue preparation for immunocytochemistry
The vervet (n = 3) and cynomolgus monkeys (n = 3) were
painlessly killed under deep anesthesia, to provide tissue for this and
other unrelated studies. Their brains were fixed by transcardial
perfusion of 500 ml heparinized saline (0.9%) followed by 2000 ml of
fixative consisting of 4% paraformaldehyde 15% saturated picric acid,
and 0.08% glutaraldehyde in 0.1 M phosphate buffer (PB),
pH 7.4. The mediobasal hypothalamus was dissected out and postfixed for
an additional 1.5 h in glutaraldehyde-free fixative. Tissue blocks
were washed and stored in 0.1 M PB at 4 C. Coronal sections
(50 µm) were cut using a Vibratome (Lancer, St. Louis, MO). Following
several rinses in PB, sections were washed for 20 min in 1% sodium
borohydride-PB to eliminate unbound aldehydes.
Immunocytochemistry for bright field microscopy
The brain sections were incubated with the primary antisera
(rabbit anti-UCP2, 1:500; 12, 13) for 24 h at room temperature.
After several washes with PB, sections were incubated in the secondary
antibody (biotinylated goat antirabbit IgG; 1:250 in PB; Vector Laboratories, Inc., Burlingame, CA) for 2 h at room
temperature, then rinsed in PB three times 10 min each time, and
incubated for 2 h at room temperature with
avidin-biotin-peroxidase (ABC, 1:250 in PB; ABC Elite Kit, Vector Laboratories, Inc.). The immunoreaction was visualized with a
modified version of the nickel-diaminobenzidine (Ni-DAB) reaction (15
mg DAB, 0.12 mg glucose oxidase, 12 mg ammonium chloride, 600 µl 0.05
M nickel ammonium sulfate, and 600 µl 10%
ß-D-glucose in 30 ml PB) for 10–30 min at room
temperature resulting in a dark blue reaction product. In control
studies in which the primary antisera was omitted or preabsorbed with
its target peptide, no immunostaining could be seen. Additional testing
of this affinity-purified antiserum has been performed in previous
studies (12, 13).
Immunocytochemistry for epifluorescence microscopy
To test for the phenotypes of UCP2-containing brain and
pituitary cells, we used the multiple labeling epifluorescence
technique to visualize two tissue antigens in the same axons or
perikarya. This procedure is similar to the one described in Horvath
et al. (12) and targeted the visualization of
UCP2 and neuropeptides of the hypothalamus that were found to be
coproduced with UCP2 in the rat (12) and also candidate
hormone-producing cells of the anterior and intermediate lobes of the
pituitary, including those producing GH or POMC. In short, vibratome
sections of either the hypothalamus or pituitary were double
immunostained for UCP2 and either neuropeptide Y (NPY), CRF, oxytocin
(OT), vasopressin (VP), GH, or POMC. Antisera were purchased from
commercial vendors [sheep anti-NPY(Auspep Pty Ltd., Perkwille,
Australia), mouse anti-CRF (Biogenesis, Pool, UK), mouse
antivasopressin (ICN Biochemicals, Costa Mesa, CA), mouse
anti-OT (DiaSorin, Inc., Stillwater, MN), mouse anti-GH
(Sigma, St. Louis, MO) and mouse anti-ß-endorphin
(Roche Molecular Biochemicals, Mannheim, Germany).
Double-labeled sections were analyzed using an Olympus Corp. upright microscope furnished with accessories enabling
epifluorescence microscopy and filters selective for the emission of
rhodamine and fluorescein. Control experiments included omission of
either of the primary antisera or the use of primary antisera
preabsorbed with the peptide against which it was generated. In these
control experiments, only single labeling could be detected.
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Results |
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, the hybridization
product was found most extensively over cells in the paraventricular,
supraoptic, and suprachiasmatic nuclei of the hypothalamus (Fig. 1, A–D). In addition, there was a small population of cells within the
arcuate nucleus that also expressed UCP2 mRNA (Fig. 1D). A more robust
expression of UCP2 message was detected in the pituitary gland,
especially in the anterior lobe (Fig. 1E). No specific labeling of UCP2
mRNA was detected in the posterior lobe, while the adjacent pia mater,
on the edge of the posterior pituitary, showed UCP2 mRNA labeling (Fig. 1E). In the anterior lobe, the hybridization product was distributed in
a heterogeneous manner creating a "W"-like appearance (Fig. 1E).
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Central nervous system. UCP2-containing axons were
detected in divergent hypothalamic and limbic sites corresponding to
the projection fields of the regions where UCP2 mRNA and peptide were
found in neuronal cell bodies (Figs. 2, 3, and 4).
These areas included the lateral septum, medial septum-diagonal band of
Broca region, bed nucleus of the stria terminalis, the stria
terminalis through its entire length, the organum vasculosum of
the laminae terminalis, anteroventral periventricular area, medial
preoptic area, periventricular regions, anterior hypothalamus,
suprachiasmatic nucleus, retrochiasmatic area, supraoptic,
paraventricular, arcuate, ventromedial, dorsomedial nuclei, lateral
hypothalamus, external and internal layers of the median eminence,
central and medial nucleus of the amygdala, and mediodorsal and
paraventricular nuclei of the thalamus (
Figs. 2–4).
UCP2-immunoreactive axon terminals established basket-like structures
around the perikarya of postsynaptic neurons in different hypothalamic,
limbic and brain stem sites (Fig. 2D). In the external layer of the
median eminence, portal capillaries were surrounded by numerous boutons
immunolabeled for UCP2 (Fig. 2E).
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and 4). These regions included the
parabrachial nucleus, area postrema, nucleus of the solitary tract, the
spinitrigeminal tract, the raphe nucleus, locus coeruleus and the
dorsal motor root ganglion of the vagus. In all of the previously
mentioned regions, an abundance of UCP2-containing axonal processes was
detected (Figs. 3 and 4). In none of the brain sites did glial elements
appear to be expressing UCP2. Only a few neuronal perikarya were found
to be labeled for UCP2 in the supraoptic, paraventricular,
suprachiasmatic and arcuate nuclei of the hypothalamus, in the lateral
hypothalamic nucleus and in the lateral parabrachial nucleus of the
brain stem (Fig. 3E).
Pituitary. Analysis of UCP2-immunolabeling in the pituitary
revealed robust expression of this mitochondrial uncoupler in a large
population of cells of the anterior pituitary and in the intermediate
lobe (Fig. 5). In the latter, the
distribution of immunolabeled cells was homogeneous and appeared to be
present in most of the cells (Fig. 5, D and E). In the anterior
pituitary, in agreement with the in situ hybridization
studies, the vast majority of labeled cells occupied a W-shaped area
(Fig. 5, B and C) corresponding to acidophilic areas (14).
In the posterior lobe, UCP2 immunolabeling was present in axonal
processes only (Fig. 5, F and G) and the pituicites, the glial cell
type of the posterior pituitary, lacked specific UCP2 labeling.
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, A and B). Several axonal processes
passing through this region and in the external layer of the median
eminence were immunolabeled for CRF (Fig. 6, C and D). In the posterior
pituitary, a population of UCP2-immunoreactive axons was also labeled
for either oxytocin (OT; Fig. 6, E and F) or vasopressin (VP; Fig. 6, G
and H).
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). On the other hand, UCP2-producing
perikarya were frequently in direct apposition to GH-immunopositive
cells (Fig. 7, A–I). During this survey, while detecting 4,000
GH-immunoreactive cells, 1,419 UCP2-immunolabeled cells were
documented, which represents an approximate 1:3 ratio of UCP2- to
GH-producing anterior pituitary cells.
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). In the
anterior pituitary, there were subpopulations of POMC neurons
distributed mainly along the lateral edges of the anterior pituitary
that also expressed UCP2 immunolabeling (620 of the 700 POMC cells
counted; Fig. 8, A and B), while a large number of both POMC (974 out
of 1400) and UCP2 (775 out of 1300) cells were only single labeled in
other parts of the anterior pituitary (Fig. 8, C–H). In this study,
the ratio of UCP2 to POMC-producing cells in the anterior pituitary was
found to be approximately 1:1.
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, I and J). The
intense labeling of both of these antigens delineated the entire
intermediate lobe. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a recent study, UCP2 was detected in neuronal populations producing
different neuropeptides that are critical for the maintenance of
homeostasis (12). These neuromodulators and hormones
included vasopressin and oxytocin in the magnocellular paraventricular
and supraoptic nuclei, CRH-producing cells in the parvicellular
paraventricular nucleus and NPY-producing neurons in the arcuate
nucleus. These same peptide systems were found to be coproduced in the
primate brain UCP2 system as well, further indicating that this
mitochondrial mechanism represents an evolutionary conserved mechanism
normally restricted to those brain circuits that govern autonomic,
endocrine and metabolic processes. On the other hand, it may be of
significance to note that, possibly due to the significantly increased
size of the primate hypothalamus (and diencephalon in general) compared
with that of the rodent, the abundance of UCP2 expression seemed
somewhat more modest in the primate when compared with the rodent
(compare Fig. 4, A and B in the current report with Fig. 1K in Ref.
12). Whether this apparent species difference is significant and might
have functional relevance regarding UCP2’s function in the brain needs
to be determined.
One of the novel observations of the present study, which was not addressed in previous experiments, is the demonstration of a robust UCP2 expression in the pituitary. It is particularly noteworthy because the level of UCP2 mRNA expression in this endocrine gland was more impressive than those found in any other parts of the central nervous system. The immunocytochemical data confirmed the widespread expression of UCP2 in all regions of the gland, including cells of the anterior and intermediate lobes and axons of the posterior pituitary. In the anterior pituitary, UCP2 was expressed predominantly in the lateral wings of the acidophilic areas. Interestingly, the most abundant cell type of this region, the GH-producing cells, lacked labeling for UCP2, while a subset of corticotrophs was found to be UCP2-producing.
In light of available information (14), the likely cell types that express UCP2 in these areas are the gonadotrophs and the lactotrophs, because thyrotrophs are most abundant in the medial zone, also called the basophilic wedge, where little evidence of UCP2 expression was found. It should be possible to resolve this issue when heterologous antisera for UCP2 and gonadotrophs or PRL become available. It should also be emphasized that none of the coexpression analyses described in the present study were truly quantitative. Therefore, future studies using a larger number of animals from different experimental conditions should provide better insight into the phenotype of UCP2-producing anterior pituitary cells, and should help to elucidate the regulatory mechanisms that determine UCP2 expression in the pituitary.
Because UCP2-immunolabeling in the posterior lobe was associated with OT- and VP-releasing axons, it may be that central UCP2 is involved in the regulation of some function of the posterior pituitary, such as water homeostasis and lactation (12). The marked expression of UCP2 in all cells of the intermediate lobe raises the possibility that UCP2 may regulate the production and secretion of the products of the POMC gene, which are intimately involved with a variety of homeostatic functions. Indeed, most of the UCP2-containing cells in this region were confirmed as being immunopositive for POMC.
Functional implications
A putative function of uncoupling proteins was first proposed for
UCP1 in brown adipose tissue (3). It was postulated and
then proven that this mitochondrial device dissipates energy generated
through the Kreb’s cycle, in the form of heat (15, 16, 17, 18).
In small rodents, this is a critical mechanism in the maintenance of
appropriate core body temperature (19). However, while
brown adipose tissue is also present in humans, particularly in early
childhood, this tissue mass is very small and does not significantly
contribute to the maintenance of core body temperature
(19). In any case, because of similarities in genetic
sequence, UCP2 was also proposed to be a mitochondrial uncoupler
(6). In fact, in transfected yeast and in in
vitro systems, UCP2 was shown to be a functional uncoupler
(6, 20) and thus, it was proposed that it might act like
UCP1 in tissues, such as the muscle, heart, spleen, and brain (6, 20). Supporting that notion, in a recent study, we revealed a
significant and positive correlation between regional mitochondrial
uncoupling activity and temperature and UCP2 protein expression in the
rat brain (12). Temperature differences between various
brain areas also exist in primates, including humans as shown by both
invasive and noninvasive techniques (21, 22, 23, 24, 25). Although the
mechanisms behind that dorso-ventral heat gradient in the brain is not
clear, it has been proposed that both heat conductance via the
skull and regional differences in blood-perfusion are most probably
involved. The detection of UCP2 in the nonhuman primate brain, in the
present study, suggests that uncoupled mitochondria in the hypothalamus
may also contribute to the generation and maintenance of local
hypothalamic temperature.
While uncoupling of the oxidative chain from ATP synthesis predicts that energy may be dissipated in the form of heat, the resulting temperature elevation might not be sufficient to significantly alter biochemical mechanisms even in the vicinity of the produced heat. In fact, the putative functions of uncoupling proteins are not limited to heat production but include the regulation of cellular ATP production, and because uncoupling proteins regulate the efficacy of oxidation, they suppress the generation of reactive oxygen species (26). This mechanism could play a critical role in the protection of cells against degeneration that can occur naturally during aging or during pathological conditions. In this regard, it is interesting to note that the expression of UCP2 in the primate brain was associated with those hypothalamic nuclei that are critically important to the minute by minute regulation of the homeostasis, including the paraventricular-, supraoptic-, suprachiasmatic-, and arcuate nuclei but was notably absent in the GH-producing anterior pituitary cells, which are known to deteriorate during aging.
It is interesting to note that while UCP1 and most of the other UCPs, including UCP3, UCP4, and BMCP1 are predominantly associated with only one or two tissue types, UCP2 is more ubiquitous being expressed in the brain and in several peripheral tissues (3, 4, 5, 6, 7, 8, 9, 10). Regardless of the principle mechanism of action of UCP2, it is likely to serve different functions in the brain and pituitary than in the periphery. For example, while UCP2 may contribute significantly to energy dissipation in the muscle and adipose tissue, its ability to reduce body weight through its brain and pituitary activity must be negligible. Instead, it is likely that UCP2’s function in homeostatic circuits relates to the fine regulation of the signaling flow within these neuronal pathways. That, however, will most likely have an impact on behavior and endocrine mechanisms relating to peripheral metabolism. In this regard, it may be of significance to note that a strong and abundant expression of UCP2 was found in the hypothalamic NPY circuitry that has been implicated as one of the key regulators of metabolism (27). In future studies, it will be important to establish the parent cells of origin of these NPY projections, which may be located either in the arcuate nucleus and/or other brain sites, including the brain stem. By regulating ATP sources of peptidergic circuits, UCP2 could ultimately affect the threshold of these peptidergic pathways in responding to different environmental stimuli. Also, because UCP2 can reduce free-radical production (26, 28), its expression in key hypothalamic circuits of homeostasis may help to protect these neuronal populations from degeneration. Additionally, as was proposed recently (12), the potential ability of UCP2 to acutely affect local temperature in axon terminals as well as to regulate the local calcium milieu, suggests that this mechanism may be involved in direct regulation of synaptic transmission and/or in the regulation of neurohormone release (CRF, OT, VP) into fenestrated capillaries and the activity of the NPY circuitry to regulate feeding behavior.
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Footnotes |
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2 Supported by a Research Grant from Wyeth-Ayerst
Women’s Health Research Institute.
Received April 18, 2000.
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