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Departments of
* Endocrinology,
Molecular Biology, and
Bioassay and Bioimage, Genentech, Inc., South San Francisco, California 94080, USA
2Correspondence: Department of Endocrinology, Genentech, Inc., M/S-37, 1 DNA Way, South San Francisco, CA 94080, USA. E-mail:jgpan{at}gene.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Key Words: uncoupling proteins • metabolism • thermoregulation • mitochondrial membrane potential
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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. The UCPs may be
responsible for proton leaks observed in the major oxygen-consuming
tissues, including brain, liver, kidney, and muscle (2
, 3)
, and thus provide novel molecular targets for regulating
energy expenditure.
UCP1, the prototype of the UCP family, is only present in brown
adipocytes and is highly inducible by norepinephrine, retinoic acid,
thyroid hormone, or cold acclimation (1)
. Mice lacking
UCP1 gene are cold-intolerant, indicating UCP1 plays an essential role
in adaptive thermoregulatory heat production (4
, 5)
. In
contrast, UCP2 is widely distributed in many tissues whereas UCP3 is
mainly expressed in skeletal muscle and brown fat (6
7
8
9)
.
UCP2 and UCP3 have been suggested as candidate genes for susceptibility
to obesity and diabetes because of their chromosomal location and
tissue distribution patterns (6
, 9
10
11
12
13
14
15)
. Indeed, the gene
expression of UCP2 and UCP3 is modulated by dietary and hormonal
manipulations including thyroid hormone, ß3-adrenergic agonists, and
leptin (7
, 9
, 16
17
18
19)
. However, the reported expression
patterns of UCP2 and UCP3 are in some respects paradoxical. For
instance, UCP2 expression in white adipose tissue and liver is
up-regulated in obesity (7
, 20)
, whereas muscle UCP3 rises
in response to fasting (9
, 21
, 22)
. Furthermore, cold
exposure fails to induce UCP3 expression in skeletal muscle
(22)
or UCP2 mRNA in brain (23)
. These
findings suggest that other putative UCP homologues may be important in
mediating metabolic changes in response to nutritional conditions or
cold temperature. Recently, we reported the discovery of another UCP
homologue, termed UCP4 (24)
. UCP4 mRNA is only detected in
the brain and its expression in mammalian cells reduces mitochondrial
membrane potential. Herein, we have further characterized UCP4 and a
newly described member of the UCP family, termed UCP5 (also termed
brain-specific mitochondrial carrier protein-1 or BMCP1, 25).
Consistent with its observed uncoupling activity in yeast
(25)
, we show that expression of UCP5 in mammalian cells
substantially reduces mitochondrial membrane potential. Furthermore,
multiple isoforms of UCP5 exist and are expressed tissue specifically.
The mRNA abundance of UCP4 and UCP5 is modulated by nutritional and
temperature manipulations in a tissue-specific manner, supporting the
hypothesis that these proteins are involved in metabolic adaptations
associated with such conditions.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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).
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Northern blot analyze
Human and mouse multiple tissue, and human multiple cancer cell
line Northern (mRNA) blots (Clontech, Palo Alto, Calif.) were probed
with the full-length human or mouse UCP5 cDNA according to the
manufacturer’s instructions. The blots were subsequently hybridized
with ß-actin cDNA.
Cell transfection and measurement of mitochondrial membrane
potential
Human embryonic kidney 293 cells were grown in culture medium
(HGDMEM, 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml
penicillin, 100 µg/ml streptomycin) to 60–80% confluence in 100 mm
plates. Cells were cotransfected with 1–1.5 µg pGreen Lantern-1
(Gibco BRL, Grand Island, N.Y.) and 7.5 µg UCP5, UCP3 constructs or a
vector control plasmid using FuGENE 6 transfection reagent according to
manufacturer’s instructions (Boehringer Mannheim, Mannheim, Germany).
The transfected cells were harvested 24 h post-transfection,
resuspended in 1 ml culture medium containing 150 ng/ml TMRE
(tetramethylrhodamine ethyl ester, Molecular Probes, Eugene, Oreg.),
and incubated for 30 min at 37°C in the dark. The cells were then
washed with 2 ml culture medium, resuspended in 1 ml culture medium,
and analyzed by flow cytometry. Transfected cells were identified based
on the expression of the green fluorescence protein (GFP). Analyses of
the samples were performed on an EPICS Elite-ESP (Beckman-Coulter,
Fullerton, Calif.). Samples were analyzed using two spatially separated
lasers. The primary laser was an argon-ion laser with fluorescence
excitation at 488 nm. The second laser was an argon-ion laser with
fluorescence excitation at 531 nm. Fluorescence emission was detected
at 525 nm and 575 nm, respectively. At least 100,000 cells were
collected in the Jurkat cell gate.
In vivo animal studies
Unless otherwise noted, mice were provided normal rodent chow
(Ralston Purina Rodent Chow 5010) and water ad libitum;
12:12 light: dark cycle (18:00–06:00 dark cycle). Animals were killed
under CO2 just prior to tissue harvest, which
occurred in the morning (08:00–12:00) unless otherwise noted. Mice
were from Jackson Labs (Bar Harbor, Maine), except FVB-N mice used in
temperature work were from Taconic (Germantown, N.Y.). Although various
tissues were collected at the end of each study, we focused on
measuring the abundance of UCP5 and UCP4 mRNA in the liver and brain.
mRNA abundance was determined using a real time quantitative
reverse-transcriptase polymerase chain reaction (RT-PCR) using primers
and probes specific to either UCP4 or UCP5 (see below).
For the fed/fasted/refed studies, 7-wk-old C57BL/6J male mice were used. Mice arrived 1 wk prior to initiation of study. At 7 wks of age, mice were randomly assigned to one of the following groups: fed ad lib, fasted 24 h or fasted 24 h, then refed ad lib 24 h.
For high-fat/low-fat studies, 4-wk-old A/J or C57BL/6J male
mice were received and placed immediately onto either a high-fat or
low-fat diet (Research Diets, Inc., New Brunswick, N.J.) patterned
after those formulated by R. D. Surwit (13)
containing 58% or 11% fat (% calories), respectively. Animals were
fed ad lib prior to tissue harvest 3 wk later (days 22–23 on diet),
when they were 7 wk old.
For temperature challenge studies, male FVB-N mice were received newly postweaned at 3 wk of age. Mice were randomly assigned to the following groups (housed 2/cage): Control (housed at 22°C 3 wk); Warmth-Acclimated (housed at 33°C for 3 wk); Food-Restricted (housed at 22°C for 3 wk, but given access each day to the average amount of food eaten by Warmth-Acclimated mice the day before); and Cold-Challenged (housed at 22°C 3 wk prior to initiation of cold exposure). All tissues were harvested at 6 wk of age; for the Cold-Challenged group, beginning in the morning mice were placed into a 4°C room for 1, 6, 24, or 48 h prior to tissue harvest and fed ad lib. Body temperature was monitored.
Total RNA extraction and real time quantitative RT-PCR
Total tissue RNA was extracted using total RNA Isolation reagent
(Biotecx Lab, Inc., Houston, Tex.) according to manufacturer’s
instructions. For real time RT-PCR, the extracted RNA was then treated
with DNase I (Gibco BRL) to remove DNA contained in the extract. Gene
expression analysis for both UCP4 and UCP5 was performed as described
previously (26
, 27)
. Primers and probes were designed
using Primer Express Software (PE Applied Biosciences, Foster City,
Calif.). For mouse UCP4: forward primer, 5'-AAT GCC TAT CGC CGA GGA
G-3'; reverse primer, 5'-GTA GGA ACT TGC TCG TCC GG-3'; probe: 5'-(FAM)
TGC TGC CGC TCA CGC AGA GAT G (TAMARA)-3'. For mouse UCP5L: forward
primer, 5'-AAA TTT GCA ACG GCG GC-3'; reverse primer, 5'-TCA GAC CAG
ACA TTT CAT GGC T-3'; probe, 5'(FAM)-TGA TTG TAA GCG GAC ATC AGA AAA
GTT CCA CTT T-(TAMARA)3'. For total mouse UCP5: forward primer, 5'-GGG
TGT GGT CCC AAC TGC T-3'; reverse primer, 5'-TTC TTG GTA ATA TCA TAA
ACG GGC A-3'; probe, 5'(FAM)-CGT GCT GCA ATC GTT GTG GGA GTA
GAG-(TAMARA)3'. For mouse ß-actin: forward primer, 5'-GAA ATC GTG CGT
GAC ATC AAA GAG-3'; reverse primer, 5'-CTC CTT CTG CAT CCT GTC AGC
AA-3'; probe, 5'(FAM)-CGG TTC CGA TGC CCT GAG GCT C(TAMARA)-3'. For
human UCP5L: forward primer, 5'-GGA ATA ATC CTA ATT TTT CTA AGG GTG
A-3'; reverse primer, 5'-CTT TTC TGG TGT CCG CTT ACA A-3'; probe,
5'(FAM)-TTT GCA ACG GCG GCC GTG-(TAMARA)3'. For human UCP5SI: forward
primer, 5'-GGG TCT GTG GAG GTG CTT ATG-3'; reverse primer, 5'-TGG GAT
TAC AGG CAT GAG CC-3'; probe, 5'(FAM)-CAA AAG CTG TTA CCG GCT GTG TGC
TG-(TAMARA)3'. For total human UCP5: forward primer, 5'-GGA TGT TCC ATG
CGC TGT T-3'; reverse primer, 5'-CGC AGG AGC AAT TCC TGA A-3'; probe,
5'(FAM)-CGC ATC TGT AAA GAG GAA GGT GTA TTG GCT CTC-(TAMARA)3'.
The thermal cycling conditions were as follows: 15 min at 50°C and 10 min at 95°C, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. All reactions were performed using Model 7700 Sequence Detector (PE Applied Biosciences). ß-Actin was used to normalize for differences in the amount of mRNA in each reaction, as its abundance was not affected by treatments (not shown). Each RNA sample was run in duplicate and the mean values of the duplicates were used to calculate the gene expression level.
To determine tissue distribution of UCP5 in human, total RNA from various human tissues (Clontech) were analyzed by a real time quantitative RT-PCR assay, with 18S used as a normalization control (primers and probes purchased from PE Applied Sciences). The relative abundance of UCP5S was obtained by subtraction of the UCP5L level from the total UCP5 level.
Statistical analysis
Values presented represent the mean ± SE of at
least five independent measures/treatment. Statistical differences
across treatments were determined using a protected Fisher’s least
significant difference analysis. In the graphs, asterisks indicate a
significance level of at least P<0.05.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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.
The ORF of the human isoform L encoded a protein of 325 amino acids.
Database searches, protein sequence alignment, and comparative analyses
revealed that hUCP5L is identical to a recently reported protein,
hBMCP1 (with one amino acid difference, Val-180; 25), and mostly
related to the established UCPs, possessing 39% amino acid identity to
the recently identified human UCP3 and UCP4. Based on its protein
sequence, broad distribution pattern, and biochemical activity (see
below), this molecule was termed uncoupling protein-5, or UCP5. Mouse
UCP5S is identical to the sequence reported for mBMCP1
(25)
. Like other UCPs, UCP5L possesses six putative transmembrane domains, three mitochondrial transporter signature motifs, and a putative nucleotide binding site. However, UCP5 has a unique hydrophobic amino-terminal sequence (22 amino acids) that is not present in the other UCPs. The function of this sequence is unknown, but may be involved in membrane anchorage. The second isoform, UCP5S, was shorter than UCP5L by three amino acids (amino acids 23–25, VSG of UCP5L). The third isoform, UCP5SI, had a 31 amino acid insertion between transmembrane domains III and IV in addition to the lack of the tri-amino acids 23–25 (VSG). This insertional sequence also contained a hydrophobic segment that may also be involved in interaction with mitochondrial membrane. The UCP5L and UCP5S protein sequences were highly conserved between human and mouse, with only eight conserved amino acid changes.
Tissue distribution of UCP5
To examine the expression pattern of hUCP5 transcripts, three
human multiple tissue Northern blots and a cancer cell line blot were
hybridized with hUCP5 cDNA probe. Two transcripts of 1.7 and 2.4 kb
were detected in multiple tissues and cancer cell lines, with the most
abundance in the brain and testis and a lower level of abundance in the
other tissues (Fig. 2A
, B
, C
, D
). Further Northern blot analysis using two brain
multiple tissue blots revealed that UCP5 transcript (1.7 kb) was
present in most regions of the brain, with low levels found in spinal
cord and corpus callosum (Fig. 2E, F
). When a mouse multiple
tissue Northern blot was analyzed, mUCP5 transcripts were similarly
detected in heart, brain, liver, kidney, and testis (Fig. 2G
). These broad expression patterns in human are different
from those reported for hBMCP1, which was reported to be expressed only
in human brain (25)
. The wide tissue distribution of UCP5
suggests that it may potentially play an important role in maintenance
of the metabolic rate should it act to uncouple respiration in
vivo.
|
To examine the relative abundance of UCP5 isoforms, a real time
quantitative RT-PCR assay was performed employing primers and probes
with specificities toward total UCP5, UCP5L, or UCP5SI and using RNA
from various human and mouse tissues. Consistent with the Northern blot
analyses, abundant UCP5 mRNA was detected in human brain, testis,
kidney, uterus, heart, lung, stomach, liver, and skeletal muscle
(Table 1
), with the greatest expression in brain and testis. In mouse, UCP5 was
detected in brain, testis, white adipose tissue, kidney, brown adipose
tissue, skeletal muscle, liver, and heart, with UCP5S being the
predominant form (Table 1)
. The relative abundance of UCP5L and UCP5S
is dramatically different between human and mouse. In general, UCP5L is
more abundant in human than in mouse tissues, ranging from 12%
(kidney) to 100% (brain) of the total UCP5 mRNA (Table 1)
. Human
skeletal muscle had approximately equal amounts of UCP5L and S. UCP5L
is the predominant form in human brain, whereas 98% of the UCP5 mRNA
is UCP5S in mouse brain. Furthermore, UCP5S is predominant in all the
other tissues examined. For instance, 85% of the UCP5 mRNA is UCP5S in
human liver, and UCP5L is detectable only in mouse brain and white
adipose tissue (Table 1)
. A trace amount of UCP5SI is present in human
substantia nigra and hippocampus but was undetectable in all other
tissues (not shown). It is probable that this isoform is only expressed
under certain conditions. Consistent with its being a rare transcript,
the cDNA encoding mouse UCP5SI has not been identified. Although the
functional significance of this tissue-specific distribution of UCP5
isoforms is unknown, it is conceivable that this unique expression
pattern may provide a mechanism to fine-tune the biological activities
of UCP5.
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Ectopic expression of UCP5 in mammalian cells resulted in decreased
mitochondrial membrane potential
The biochemical activities of UCPs have been studied in both
mammalian and yeast cells (1
, 6
, 7
, 24
, 28)
. Expression of
the known UCPs in these cells leads to a decline in mitochondrial
membrane potential (MMP), suggestive of an uncoupling activity
(1
, 6
, 7
, 9
, 22
, 24
, 28)
. TMRE is a fluorescent dye that
has been used to monitor the mitochondrial membrane potential changes
in intact cells (22)
. To test whether UCP5, like other UCP
homologues, lowers mitochondrial membrane potential, human embryonic
kidney 293 cells were cotransfected with a GFP expression construct and
a control vector or DNA construct expressing UCP3 or UCP5L. Relative to
the vector-transfected cells, expression of UCP3 in the 293 cells
induced a dramatic shift in fluorescence intensity, indicative of a
membrane potential decline (Fig. 3A, B
). Expression of UCP5L in the same cells led to a similar
change (Fig. 3)
. These findings suggest that UCP5L is a functional
uncoupling protein, which is consistent with uncoupling activity
reported for BMCP1 (25)
.
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UCP3 and UCP4 were localized to the mitochondrial membrane and an
NH2-Flag tag did not affect their uncoupling
activity or mitochondrial localization (24)
. In contrast,
an NH2 tag completely abolished the uncoupling
activity of UCP5L and its mitochondrial localization (data not shown),
suggesting that the unique NH2 sequence of UCP5
may be important for its localization and/or activity.
Isoforms of UCP5 showed different potency in reducing mitochondrial
membrane potential
To examine whether different isoforms of UCP5 were functionally
different, we compared their ability to reduce membrane potential.
Although cells transfected with hUCP5S displayed a significant shift in
TMRE fluorescence, indicating a drop in membrane potential, the
magnitude of the changes was less than that observed for hUCP5L (Fig. 3C
). A similar observation was made for mUCP5L and mUCP5S
(Fig. 3C
). Note that uncoupling activity has been reported
for mBMCP1/mUCP5S (25)
. These findings suggest that
whereas UCP5S lowers MMP, the tri-amino acid (VSG) deletion may
interfere with its putative uncoupling activity.
hUCP5SI showed an activity comparable to that of hUCP5L (Fig. 3C
). Elevated expression of UCP5 in these transfected cells
was confirmed by real time quantitative RT-PCR, and no differences were
observed among isoforms (not shown). The mechanism by which the
deletion or the insertion affects biochemical activity is currently
unknown. It is conceivable that these alterations may influence UCP5
interaction with the mitochondrial inner membrane or its conformation,
thereby impairing its efficiency as a proton transporter. The existence
of multiple isoforms with tissue-specific expression and different
effects on membrane potential suggests the complexity of the UCP5
uncoupling system; the differential expression of the isoforms may
provide a mechanism to modulate UCP5 function in vivo.
Down-regulation of UCP5 expression in liver induced by fasting
Fasting is known to lower body metabolic rate, although the
underlying molecular mechanisms are unclear. UCPs have been implicated
in the maintenance of metabolic rate. To better understand whether UCP4
and UCP5 are involved in this process, we subjected mice to fasting,
and gene expression (mRNA) in the liver and brain was monitored by a
quantitative RT-PCR analysis (see Materials and Methods). A 24 h
fast in C57BL/6J mice significantly lowered liver UCP5 mRNA levels
(Fig. 4A
). Remarkably, refeeding restored liver UCP5 mRNA to the
control level. These data support the hypothesis that UCP5 is involved
in changes in metabolic rate associated with fasting and refeeding,
especially in light of the significant metabolic contribution of the
liver. The brain UCP4 and UCP5 mRNA levels were not significantly
affected (Fig. 4B
).
|
Up-regulation of liver UCP5 mRNA in A/J mice by a high-fat diet
A/J mice have been shown to be obesity resistant on a high-fat
diet compared to the obesity-prone C57BL/6J mice, apparently due to
differences in metabolic efficiency (17)
. Adipose tissue
UCP2 expression was found to be up-regulated in A/J mice but not in
C57BL/6J mice fed a high-fat diet (17)
. We tested whether
a similar regimen would also affect UCP4 and 5 expression
differentially in these strains. A high-fat diet significantly
increased UCP5 mRNA level (1.6-fold) in the liver of A/J but not
C57BL/6J mice when compared to a low-fat diet (Fig. 5A
), suggesting UCP5 expression in C57BL/6J mice may be less
responsive to the high-fat diet. Such responses for UCP5 expression in
the liver of A/J vs. C57BL/6J mice are consistent with the notion that
UCP5 activity may contribute to the differences in their metabolic
efficiency. No significant effects were observed for UCP4 and UCP5 mRNA
abundance in the brain (Fig. 5B
).
|
A rapid rise in both UCP4 and UCP5 mRNA levels induced by cold
exposure
It is well established that cold exposure in rodents elicits
a rise in metabolic rate, presumably to sustain a stable body
temperature. The extent to which mitochondrial uncoupling underlies
changes in metabolic rate remains an open question. UCP1 expression in
brown adipose tissue is highly induced by cold acclimation
(1)
. Local heat production has been observed in the brain
in response to cold (29)
. Since both UCP4 and UCP5 are
highly expressed in the brain where the thermoregulatory signals are
originated, we tested whether UCP4 and UCP5 expression could be
modulated by cold exposure. On cold exposure, brain UCP4 rose
significantly and remained elevated from 1 h at least through
24 h, whereas UCP5 mRNA in brain and liver increased at 1 h
and remained elevated through at least 6 h (Fig. 6A, B
). Although brain temperature was not monitored, note
that changes in body temperature were preceded by a rise in UCP4 (in
brain) and UCP5 (in brain and liver) expression (Fig. 6B
).
For instance, body temperature dropped by 2°C at 1 h cold
exposure, started to recover at 6 h, and was restored to normal at
48 h (see Fig. 6B
legend). Note that total brain was
assayed for UCP4 and 5 mRNA, and it is conceivable that more localized
changes could have occurred. Warmth acclimation or chronic food
restriction did not result in any significant changes in UCP4 and UCP5
mRNA levels. Since UCPs are thought to uncouple the process of
mitochondrial respiration from oxidative phosphorylation and dissipate
energy as heat, these findings suggest that UCP4 and UCP5 may play an
important role in thermoregulatory processes induced by cold exposure.
|
In summary, we have characterized UCP5/BCMP-1, a newly described member of the UCP family, and found that the expression of UCP4 and UCP5 are modulated tissue specifically by fasting, a high-fat diet, and cold exposure. Consistent with its being an uncoupling protein, expression of UCP5 reduces mitochondrial membrane potential. Like UCP2, UCP5 is expressed in multiple tissues and is up-regulated in liver by high-fat diet selectively in obesity-resistant A/J, but not C57BL/6J mice. Liver UCP5 mRNA was down-regulated by fasting and restored after refeeding. Moreover, expression of UCP5 in liver and brain and of UCP4 in brain was up-regulated by cold exposure. Note that only the total UCP5 mRNA was monitored. Preliminary analyses using mUCP5L-specific primers and probe indicated that the mUCP5L mRNA in brain was doubled on cold exposure, although liver mUCP5L was not induced (not shown). It remains to be determined whether isoforms of UCP5 are differentially regulated in other tissues by dietary or temperature manipulations. These findings are consistent with the idea that these new uncoupling homologues may mediate metabolic changes induced by fasting, a high-fat diet, and cold exposure, possibly playing an important role in local or whole body adaptational thermoregulatory processes. It is intriguing to speculate that the ability to up-regulate UCP5 may contribute to obesity resistance.
Other functions for UCP homologues may be postulated. It has been shown
that Down’s syndrome neurons have a defect in the metabolism of
reactive oxygen species (ROS), and increased ROS causes neuronal
apoptosis (30)
. UCP2 has been shown as a regulator of ROS
generation (31)
. It is tempting to speculate that these
two newly identified UCP homologues may be involved in regulation of
ROS generation and play a protective role in the brain. If true,
disruption of their normal uncoupling activities may be associated with
certain neurodegenerative disorders. Furthermore, note that UCP5 is
highly abundant in human testis. Testicular temperatures are critical
for normal spermatogenesis (32)
, and it is conceivable
that UCP5 may be involved in the regulation of local testicular
temperature
Three isoforms of UCP5 have been discovered. The existence of multiple isoforms of UCP5 suggests a complexity in the regulation of UCP5 uncoupling activity. Future studies including transgenic models and targeted gene disruption may reveal the physiological functions of these newly identified UCP homologues.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication September 10, 1999.
Revision received November 18, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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’ and leukemia inhibitory factor induce different cardiac hypertrophy phenotypes in vitro. Endocrine 9,45-55[Medline]
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