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Vol. 273, Issue 1, 5-8, January 2, 1998
From the Departments of A new member of the uncoupling protein (UCP)
family called UCP3 has recently been cloned and shown to be highly
expressed in skeletal muscle of rodents and humans. In the present
study, UCP3 was overexpressed in C2C12
myoblasts where it acts as an uncoupling protein. Changes in UCP3
mRNA expression were examined in rodent muscles under conditions
known to modulate thermogenesis in brown adipose tissue. In skeletal
muscle, UCP3 expression did not change in response to 48 h of cold
exposure (6 °C), whereas it was decreased by 81% or increased
5.6-fold by 1 week of 50% food restriction or fasting, respectively.
It was also decreased by 36% in soleus muscle of obese
(fa/fa) as compared with lean Zucker rats. The unexpected
rise of UCP3 mRNA level induced by fasting did not change in
vitro muscle basal heat production rate but decreased by 31% the
capacity to produce heat in response to the uncoupler carbonylcyanide
p-trifluoromethoxyphenylhydrazone. This decrease may
reflect underlying uncoupling by UCP3. Up-regulation of UCP3 mRNA
after a 24-h fast was still observed in mice exposed at
thermoneutrality. These results show that the increase in UCP3 expression induced by fasting is associated with the maintenance of
thermogenesis measured in muscle in vitro and is not
modulated by environmental temperature. The notion that UCP3 expression is modulated by food intake is of importance to better understand the
pathophysiology of obesity in humans.
The uncoupling protein-1
(UCP1)1 gene encodes a
mitochondrial protein carrier that stimulates heat production by
uncoupling respiration from ATP synthesis in brown adipose tissue (BAT)
and plays an important role in nonshivering and diet-induced
thermogenesis in rodents (1). Recently, new proteins sharing 55 and
56% amino acid identities with UCP1 have been identified and called
UCP2 and UCP3 (2-4). The tissue distributions of UCP2 and UCP3 were very different from that of UCP1, which is BAT-specific, being either
ubiquitous (UCP2) or specific to skeletal muscle and BAT (UCP3) (2-4).
UCP2 was shown to be an uncoupling protein because in transfected yeast
it partially uncouples mitochondrial respiration (2). The modulations
of UCP2 expression have also been studied in various tissues of the
rat. Cold exposure was found to affect UCP2 similarly to UCP1 in BAT
(5). Fasting, however, was found to up-regulate UCP2 mRNA in the
skeletal muscle (5).
The presence of UCP3 in skeletal muscle is of great interest because
this tissue is an important site of catecholamine and diet-induced
thermogenesis in rats (6) and in humans (7, 8). UCP3 might therefore
play a major role in whole body thermogenesis.
The aims of this work were: (i) to develop a cell line of
UCP3-transfected myoblasts and to examine the effects of UCP3
expression on mitochondrial membrane potential and (ii) to study
in vivo modulations of UCP3 expression in BAT and in
skeletal muscle under conditions known to affect UCP1 and UCP2. The
results obtained show that UCP3 has an uncoupling activity in
transfected myoblasts. They also demonstrate that UCP3 mRNA
expression in skeletal muscle is modulated by food intake but not by
changes in environmental temperature.
Cell Transfection--
A 0.9-kilobase pair fragment containing
the coding sequence of the human UCP3 was excised from pBluescript at
EcoRI and HindIII sites (present in the multiple
cloning site of the vector) and inserted into the
EcoRI/HindIII sites of the expression vector, pcDNA 3.1 (Invitrogen, Leek, Netherlands).
C2C12 myoblast cells were grown in Dulbecco's
modified Eagle's medium supplemented with 10% fetal calf serum and
transfected with either the empty pcDNA 3.1 or the vector
containing the human UCP3 using the calcium phosphate precipitation
method. Stable transfectants were obtained by growth of the cells in
culture medium containing 600 µg/ml G418 (Life Technologies, Inc.).
Colonies derived from single cells were isolated and expanded. Cell
lines were screened for the expression of UCP3 by Northern blot
analysis.
Confocal Microscopy--
Stable transfected
C2C12 myoblast cells were grown on 25-mm round
glass coverslips in Dulbecco's modified Eagle's medium with 10%
fetal calf serum. Cells were washed with phosphate-buffered saline and
incubated for 30 min at 37 °C with 10 nM
tetramethylrhodamine ethyl ester (TMRE) in a balanced salt
solution containing 5.5 mM glucose, 120 mM
NaCl, 4 mM KCl, 1 mM
KH2PO4, 1 mM MgSO4, 1.3 mM CaCl2, and 10 mM HEPES buffer
adjusted to pH 7.4. Confocal images were acquired with an invert laser
scan microscope (LSM 410 invert, Carl Zeiss, Germany). The cells were
excited with a HeNe 543 nm laser and observed at emission above 590 nm.
All images were acquired with the same parameters and analyzed with LSM-PC software (Carl Zeiss, Germany).
Analysis of Mitochondrial Membrane Potential by Flow
Cytometry--
Subconfluent C2C12 myoblast
cells were loaded with TMRE (10 nM) in the presence or the
absence of the uncoupler carbonylcyanide m-chlorophenylhydrazone (CCCP) (75 µM). After
30 min of incubation at 37 °C, the cells were washed, trypsinized,
and resuspended in the balanced salt solution with TMRE (10 nM). Flow cytometry was performed with a
FACStarPlus cell sorter (Becton Dickinson, Bedford, MA)
using the 514 nm line of an argon laser to assess the mitochondrial
membrane potential. Fluorescent light was directed to a photomultiplier
tube equipped with a filter selecting above 590 nm. A minimum of 10,000 cells/sample were acquired and analyzed with Lysis II software.
Animal Treatments--
7-week old Sprague-Dawley male rats or
9-week old female lean (Fa/?) and obese (fa/fa) Zucker rats
fed ad libitum standard laboratory chow were maintained
under a 12-h light-dark cycle at 23 °C. All animals were caged
individually during the experimental periods. Rats were either exposed
to cold (6 °C) or fasted with free access to water for 48 h.
Studies were also performed with adult C57BL male mice, which were fed
the same diet as the rats. They were divided into three groups: group 1 was kept at 23 °C for 1 week, group 2 was kept at thermoneutrality
(33 °C) for 1 week, and group 3 was kept at 23 °C and pair-fed
with the mice at 33 °C for 1 week. 24 h before sacrifice, half
of the mice in each group were fasted with free access to water
containing 4.5 g/liter of NaCl. The animals were killed by
decapitation, and soleus and tibialis anterior muscles, as well as
interscapular BAT carefully trimmed from white adipose tissue,
connective tissue, and muscle, were excised, immediately frozen in
liquid nitrogen, and stored at Northern Blot Analyses--
Total RNA was purified by the method
of Chomczynski and Sacchi (9), and 12-20 µg were electrophoresed in
a 1.2% agarose gel containing formaldehyde, as described by Lehrach
et al. (10) and transferred to Electran Nylon Blotting
membranes (BDH Laboratory Supplies, Poole, UK) by vacuum blotting. The
probes used were a full-length rat UCP3 cDNA (GenBankTM accession
number U92069). The UCP3 signal in rat and mouse was a doublet with
sizes of 2.5 and 2.8 kilobases as already described (3). The probe was
labeled by random priming with [ Microcalorimetric Studies--
Soleus muscle obtained from adult
mice kept at 23 °C either fed ad libitum or fasted for
24 h were mounted on a rigid frame made of thin stainless steel
thread and introduced in the test chamber of a twin microcalorimeter
(Secfroid, S.A., Lausanne, Switzerland) as described previously (11).
Both test and reference chambers were perifused with the same standard,
Krebs-Ringer bicarbonate-buffered solution containing 5 mM
glucose that was gassed continuously with a mixture of 95%
O2 and 5% CO2 at pH 7.4 and 30 °C.
COMMUNICATION
Uncoupling Protein-3 Expression in Rodent Skeletal Muscle Is
Modulated by Food Intake but Not by Changes in Environmental
Temperature*
§,,,, and
Medical Biochemistry and
¶ Physiology, Faculty of Medicine, University of Geneva, 1 Michel
Servet, 1211 Geneva 4, Switzerland
ABSTRACT
Top
Abstract
Introduction
Procedures
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References
80 °C.
-32P]dCTP (Amersham)
to a specific radioactivity of approximately 1 × 109
dpm/µg DNA. Northern blots were hybridized for 2 h at 65 °C
in QuikHyb solution (Stratagene, La Jolla, CA) and then washed in a
solution of 2 × SSC (1 × SSC is 150 mM NaCl, 15 mM sodium citrate, pH 7.0)/0.1% sodium dodecyl sulfate at
50 °C twice for 5 min and in 0.1×SSC/0.1% sodium dodecyl sulfate
at 50 °C for 5 min. Blots were exposed to Hyperfilm ECL films
(Amersham) at 80 °C with intensifying screens. Size estimates for
the RNA species were established by comparison with an RNA Ladder (Life
Technologies, Inc.). The signals on the autoradiograms were quantified
by scanning photodensitometry using ImageQuant Software version 3.3 (Molecular Dynamics, Sunnyvale, CA). Hybridization of the blots with a
[
-32P]ATP-labeled synthetic oligonucleotide specific
for the 18 S rRNA subunit was used to correct for differences in the
amounts of RNA loaded onto the gel. Student's unpaired t
test was used to determine statistical significance.
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RESULTS |
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Top
Abstract
Introduction
Procedures
Results
Discussion
References
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Effect of UCP3 Expression in Myoblasts-- C2C12 cells, which expressed low amounts of UCP2 mRNA at the myoblast stage of differentiation and no UCP3 mRNA, were transfected with either an empty vector (control) or a vector containing the human UCP3 cDNA. A cell clone was chosen in which the level of expression of UCP3 mRNA, as measured by Northern blot analysis, was as high as in human skeletal muscle. Control and transfected cells were incubated with TMRE, a fluorescent dye that is sensitive to the mitochondrial potential, i.e. to the electrochemical gradient across the mitochondrial inner membrane. Confocal microscopy studies confirmed that the fluorescence is specifically localized in mitochondria as already described (12). As expected, the specific mitochondrial uncoupler CCCP (75 µM) strongly decreased the fluorescence (Fig. 1). To evaluate the effect of UCP3 on mitochondrial membrane potential, fluorescence intensities were measured using flow cytometry in UCP3-transfected and control C2C12 cells. As shown in Fig. 2, UCP3 transfection resulted in a shift of the fluorescence peak to the left, which reflected a decrease in the level of fluorescence per cell. The mean values of 24.2 ± 0.7 (n = 3) and 18.8 ± 0.7 (n = 5) fluorescence arbitrary units in control and UCP3-transfected cells, respectively, differed significantly from each other (p < 0.0025). Addition of CCCP induced a large shift to the left in both populations of cells (p < 0.001). In fully uncoupled cells, the fluorescence peaks of control and UCP3 transfected cells were superimposed. The effect of CCCP was therefore weaker in the transfected cells than in control cells (p < 0.001), confirming the lower basal mitochondrial membrane potential in the former.
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In Vivo Modulations of UCP3 Expression-- Conditions known to modulate UCP1 expression were chosen to examine the possible changes of UCP3 mRNA expression in vivo, i.e. cold exposure and fasting. Cold exposure was found to increase UCP3 expression 1.5-fold in rat BAT (p < 0.05, n = 5; results not shown). As seen in Fig. 3A, it had no effect on UCP3 expression in rat tibialis anterior muscle. A 48-h fast was found to decrease UCP3 expression by 74% in rat BAT (p < 0.005, n = 5; results not shown); however, as seen in Fig. 3A, it increased UCP3 expression 5.6-fold in rat tibialis anterior muscle.
|
, p < 0.05 versus ad libitum fed mice at
23 °C (B). C, representative UCP3 mRNA and
18 S ribosomal RNA signals.
|
1. The number of experiments was nine
to eleven. *, p < 0.05; **, p < 0.005 versus respective controls.
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DISCUSSION |
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Top
Abstract
Introduction
Procedures
Results
Discussion
References
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Previously reported UCP1 and UCP2 transfection studies have been performed in yeast (2, 13). Because UCP3 is highly expressed in skeletal muscle (4), the putative uncoupling activity of UCP3 was investigated using a mouse myoblast cell line, C2C12. The results obtained by overexpression of UCP3 confirmed what has been inferred from sequence analysis (3), i.e. that UCP3 has uncoupling properties. Using the mitochondrial membrane potential fluorescent dye TMRE and flow cytometry, we showed that transfection of C2C12 cells with UCP3 dissipated part of the mitochondrial proton motive force. The uncoupling activity of UCP3 has recently been shown in transformed yeast (14). Our results also indicated that the degree of mitochondrial uncoupling was small as compared with the total uncoupling effect induced by CCCP. This relatively small degree of uncoupling is comparable with that previously reported for UCP1, UCP2, and UCP3 in transformed yeast (2, 13, 14), thus suggesting that the uncoupling activity is tightly controlled inside the cell. Inhibition of UCP3 activity in vivo could be mediated by GDP because a potential purine nucleotide binding site is present in the protein (3), by other nucleotides, or by as yet unidentified factors.
Under the metabolic conditions studied, i.e. cold exposure or fasting, the level of UCP3 mRNA in BAT was modulated in the same way as that of UCP1 (results not shown). Indeed, in this tissue, it has been reported that cold exposure increases (1, 6) and fasting decreases (5, 15) UCP1 expression. The striking parallelism found between UCP1 and UCP3 modulations in BAT is consistent with a role of UCP3 as an uncoupler of oxidative phosphorylation in this thermogenic tissue.
The results obtained in skeletal muscle indicate that UCP3 mRNA level was not modified by cold exposure and that the decreased UCP3 expression measured at 33 °C can be attributed to the decrease in food intake occurring at thermoneutrality (Fig. 3B). This marked decrease in UCP3 expression might contribute to the lower whole body energy dissipation induced by food restriction (16).
The results obtained in BAT and muscles of Zucker rats are also in line with a role of UCP3 as a thermogenic protein. The decrease in UCP3 observed in obese (fa/fa) rats might contribute to their decreased thermogenesis (1).
Fasting induces a paradoxical effect on UCP3 expression in muscle that is opposite to that induced by food restriction, i.e. a marked increase (Fig. 3A). Despite this increase in UCP3, fasting had no effect on in vitro soleus muscle basal heat production rate (Fig. 4). Because thermogenesis due to anabolic-catabolic pathways is probably reduced in fasted animals, the maintenance of a normal heat production rate might result from a compensatory effect by UCP3. The hypothesis of a more uncoupled state in fasted soleus muscle is supported by the observation that the mean stimulation of heat production induced by FCCP was significantly lower in fasted than in control mouse soleus muscle.
In mice kept at thermoneutrality, the increase in tibialis anterior muscle UCP3 expression induced by fasting was similar to that of control mice kept at 23 °C (Fig. 3B). This result does not support the notion that changes in muscle UCP3 level might play a role in the maintenance of body temperature.
These results indicate that the increase in UCP3 expression induced by fasting is associated with the maintenance of thermogenesis measured in muscle in vitro and is not modified by changes in the environmental temperature. They also show that different mechanisms are responsible for the control of UCP3 expression in BAT and in skeletal muscle. In BAT, the effects of cold exposure or fasting on UCP3 expression, like those on UCP1, should be mediated by an increase or a decrease, respectively, of the sympathetic nervous system activity. In muscle UCP3 expression seems not to be controlled by the same system but probably by changes in food intake among other factors.
Among the metabolic changes induced by fasting, the increase in the circulating fatty acids (17, 18) or the increase in plasma glucocorticoids (17) with no change in catecholamines (18) reported in rats fasted for 48 h could be responsible for the increase in muscle UCP3 expression. Further experiments are underway in our laboratory to elucidate this mechanism.
UCP3, being highly expressed in human skeletal muscle (3), might be an important effector of thermogenesis in humans. It is conceivable that disregulations of UCP3 activity or expression could favor body weight gain and obesity. The notion that UCP3 expression is dependent on food intake is of importance to better understand the biochemical events relating energy intake to energy expenditure.
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ACKNOWLEDGEMENTS |
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We are greatly indebted to Claudette Duret for excellent technical assistance. We are also grateful to Dominique Wohlwend for the flow cytometry analysis.
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FOOTNOTES |
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* This work was supported by Swiss National Science Foundation Grants 31-43405.95, 31-47211.96, and 31-46893.96, by the Ciba-Geigy-Jubiläums-Stiftung, and by the Fondation du Centenaire de la Société Suisse d'Assurances Générales sur la Vie Humaine pour la Santé Publique et les Recherches Médicales.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Supported by a grant from the Swiss Institute of Sport Sciences. To whom correspondence should be addressed. Tel.: 4122-702-54-87; Fax: 4122-702-55-02; E-mail: Olivier.Boss{at}medecine.unige.ch.
1 The abbreviations used are: UCP, uncoupling protein; BAT, brown adipose tissue; TMRE, tetramethylrhodamine ethyl ester; CCCP, carbonyl cyanide m-chlorophenylhydrazone; FCCP, carbonylcyanide p-trifluoromethoxyphenylhydrazone.
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H. Pilegaard, B. Saltin, and P. D. Neufer Effect of Short-Term Fasting and Refeeding on Transcriptional Regulation of Metabolic Genes in Human Skeletal Muscle Diabetes, March 1, 2003; 52(3): 657 - 662. [Abstract] [Full Text] [PDF]
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T. Teruel, R. Hernandez, M. Benito, and M. Lorenzo Rosiglitazone and Retinoic Acid Induce Uncoupling Protein-1 (UCP-1) in a p38 Mitogen-activated Protein Kinase-dependent Manner in Fetal Primary Brown Adipocytes J. Biol. Chem., January 3, 2003; 278(1): 263 - 269. [Abstract] [Full Text] [PDF]
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M.-E. Harper, R. Dent, S. Monemdjou, V. Bezaire, L. Van Wyck, G. Wells, G. N. Kavaslar, A. Gauthier, F. Tesson, and R. McPherson Decreased Mitochondrial Proton Leak and Reduced Expression of Uncoupling Protein 3 in Skeletal Muscle of Obese Diet-Resistant Women Diabetes, August 1, 2002; 51(8): 2459 - 2466. [Abstract] [Full Text] [PDF]
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P. Schrauwen and M. Hesselink UCP2 and UCP3 in muscle controlling body metabolism J. Exp. Biol., August 1, 2002; 205(15): 2275 - 2285. [Abstract] [Full Text] [PDF]
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I. Guillet-Deniau, V. Mieulet, S. Le Lay, Y. Achouri, D. Carre, J. Girard, F. Foufelle, and P. Ferre Sterol Regulatory Element Binding Protein-1c Expression and Action in Rat Muscles: Insulin-Like Effects on the Control of Glycolytic and Lipogenic Enzymes and UCP3 Gene Expression Diabetes, June 1, 2002; 51(6): 1722 - 1728. [Abstract] [Full Text] [PDF]
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 G. Argyropoulos and M.-E. Harper Molecular Biology of Thermoregulation: Invited Review: Uncoupling proteins and thermoregulation J Appl Physiol, May 1, 2002; 92(5): 2187 - 2198. [Abstract] [Full Text] [PDF]
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 V. M Rodriguez, M. P Portillo, C. Pico, M T. Macarulla, and A. Palou Olive oil feeding up-regulates uncoupling protein genes in rat brown adipose tissue and skeletal muscle Am. J. Clinical Nutrition, February 1, 2002; 75(2): 213 - 220. [Abstract] [Full Text] [PDF]
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C. M. Kotz, C. Wang, A. S. Levine, and C. J. Billington Urocortin in the hypothalamic PVN increases leptin and affects uncoupling proteins-1 and -3 in rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R546 - R551. [Abstract] [Full Text] [PDF]
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P. SCHRAUWEN, W. H. M. SARIS, and M. K. C. HESSELINK An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix FASEB J, November 1, 2001; 15(13): 2497 - 2502. [Abstract] [Full Text] [PDF]
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V. Bezaire, W. Hofmann, J. K. G. Kramer, L. P. Kozak, and M.-E. Harper Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice Am J Physiol Endocrinol Metab, November 1, 2001; 281(5): E975 - E982. [Abstract] [Full Text] [PDF]
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 P. de Lange, A. Lanni, L. Beneduce, M. Moreno, A. Lombardi, E. Silvestri, and F. Goglia Uncoupling Protein-3 Is a Molecular Determinant for the Regulation of Resting Metabolic Rate by Thyroid Hormone Endocrinology, August 1, 2001; 142(8): 3414 - 3420. [Abstract] [Full Text] [PDF]
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C. R. VIANNA, T. HAGEN, C.-Y. ZHANG, E. BACHMAN, O. BOSS, B. GEREBEN, A. S. MORISCOT, B. B. LOWELL, J. E. P. W. BICUDO, and A. C. BIANCO Cloning and functional characterization of an uncoupling protein homolog in hummingbirds Physiol Genomics, April 2, 2001; 5(3): 137 - 145. [Abstract] [Full Text] [PDF]
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 R. Weindruch, K. P. Keenan, J. M. Carney, G. Fernandes, R. J. Feuers, R. A. Floyd, J. B. Halter, J. J. Ramsey, A. Richardson, G. S. Roth, et al. Caloric Restriction Mimetics: Metabolic Interventions J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2001; 56(90001): 20 - 33. [Abstract] [Full Text] [PDF]
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 J. Himms-Hagen and M.-E. Harper Physiological Role of UCP3 May Be Export of Fatty Acids from Mitochondria When Fatty Acid Oxidation Predominates: An Hypothesis Experimental Biology and Medicine, February 1, 2001; 226(2): 78 - 84. [Abstract] [Full Text]
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Y. Hong, B. D. Fink, J. S. Dillon, and W. I. Sivitz Effects of Adenoviral Overexpression of Uncoupling Protein-2 and -3 on Mitochondrial Respiration in Insulinoma Cells Endocrinology, January 1, 2001; 142(1): 249 - 256. [Abstract] [Full Text] [PDF]
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 D. Ricquier and F. Bouillaud Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance J. Physiol., November 15, 2000; 529(1): 3 - 10. [Abstract] [Full Text] [PDF]
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S. Monemdjou, W. E. Hofmann, L. P. Kozak, and M.-E. Harper Increased mitochondrial proton leak in skeletal muscle mitochondria of UCP1-deficient mice Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E941 - E946. [Abstract] [Full Text] [PDF]
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M. Zhou, B.-Z. Lin, S. Coughlin, G. Vallega, and P. F. Pilch UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase Am J Physiol Endocrinol Metab, September 1, 2000; 279(3): E622 - E629. [Abstract] [Full Text] [PDF]
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X. X. YU, W. MAO, A. ZHONG, P. SCHOW, J. BRUSH, S. W. SHERWOOD, S. H. ADAMS, and G. PAN Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation FASEB J, August 1, 2000; 14(11): 1611 - 1618. [Abstract] [Full Text]
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X. X. Yu, J. L. Barger, B. B. Boyer, M. D. Brand, G. Pan, and S. H. Adams Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics Am J Physiol Endocrinol Metab, August 1, 2000; 279(2): E433 - E446. [Abstract] [Full Text] [PDF]
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S. Hidaka, H. Yoshimatsu, T. Kakuma, H. Sakino, S. Kondou, R. Hanada, K. Oka, Y. Teshima, M. Kurokawa, and T. Sakata Tissue-Specific Expression of the Uncoupling Protein Family in Streptozotocin-Induced Diabetic Rats Experimental Biology and Medicine, July 1, 2000; 224(3): 172 - 177. [Abstract] [Full Text]
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A. L. Hildebrandt and P. D. Neufer Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1078 - E1086. [Abstract] [Full Text] [PDF]
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 C. Bing, M. Brown, P. King, P. Collins, M. J. Tisdale, and G. Williams Increased Gene Expression of Brown Fat Uncoupling Protein (UCP)1 and Skeletal Muscle UCP2 and UCP3 in MAC16-induced Cancer Cachexia Cancer Res., May 1, 2000; 60(9): 2405 - 2410. [Abstract] [Full Text]
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 S. H. Adams Uncoupling Protein Homologs: Emerging Views of Physiological Function J. Nutr., April 1, 2000; 130(4): 711 - 714. [Abstract] [Full Text]
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C. M. Kotz, C. F. Wang, J. E. Briggs, A. S. Levine, and C. J. Billington Effect of NPY in the hypothalamic paraventricular nucleus on uncoupling proteins 1, 2, and 3 in the rat Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R494 - R498. [Abstract] [Full Text] [PDF]
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 S. B. Pedersen, K. Kristensen, S. Fisker, J. O. L. Jørgensen, J. S. Christiansen, and B. Richelsen Regulation of Uncoupling Protein-2 and -3 by Growth Hormone in Skeletal Muscle and Adipose Tissue in Growth Hormone-Deficient Adults J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4073 - 4078. [Abstract] [Full Text]
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 B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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W. I. Sivitz, B. D. Fink, D. A. Morgan, J. M. Fox, P. A. Donohoue, and W. G. Haynes Sympathetic inhibition, leptin, and uncoupling protein subtype expression in normal fasting rats Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E668 - E677. [Abstract] [Full Text] [PDF]
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M. B. Jekabsons, F. M. Gregoire, N. A. Schonfeld-Warden, C. H. Warden, and B. A. Horwitz T3 stimulates resting metabolism and UCP-2 and UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice Am J Physiol Endocrinol Metab, August 1, 1999; 277(2): E380 - E389. [Abstract] [Full Text] [PDF]
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W. I. Sivitz, B. D. Fink, and P. A. Donohoue Fasting and Leptin Modulate Adipose and Muscle Uncoupling Protein: Divergent Effects Between Messenger Ribonucleic Acid and Protein Expression Endocrinology, April 1, 1999; 140(4): 1511 - 1519. [Abstract] [Full Text]
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R. N. Cortright, D. Zheng, J. P. Jones, J. D. Fluckey, S. E. DiCarlo, D. Grujic, B. B. Lowell, and G. L. Dohm Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation Am J Physiol Endocrinol Metab, January 1, 1999; 276(1): E217 - E221. [Abstract] [Full Text] [PDF]
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L. J. Kelly, P. P. Vicario, G. M. Thompson, M. R. Candelore, T. W. Doebber, J. Ventre, M. S. Wu, R. Meurer, M. J. Forrest, M. W. Conner, et al. Peroxisome Proliferator-Activated Receptors {gamma} and {alpha} Mediate in Vivo Regulation of Uncoupling Protein (UCP-1, UCP-2, UCP-3) Gene Expression Endocrinology, December 1, 1998; 139(12): 4920 - 4927. [Abstract] [Full Text] [PDF]
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B. B. Boyer, B. M. Barnes, B. B. Lowell, and D. Grujic Differential regulation of uncoupling protein gene homologues in multiple tissues of hibernating ground squirrels Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R1232 - R1238. [Abstract] [Full Text] [PDF]
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B. Lin, S. Coughlin, and P. F. Pilch Bidirectional regulation of uncoupling protein-3 and GLUT-4 mRNA in skeletal muscle by cold Am J Physiol Endocrinol Metab, September 1, 1998; 275(3): E386 - E391. [Abstract] [Full Text] [PDF]
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P. Barbe, L. Millet, D. Larrouy, J. Galitzky, M. Berlan, J.-P. Louvet, and D. Langin Uncoupling Protein-2 Messenger Ribonucleic Acid Expression During Very-Low-Calorie Diet in Obese Premenopausal Women J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2450 - 2453. [Abstract] [Full Text]
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A. Matthias, K. B. E. Ohlson, J. M. Fredriksson, A. Jacobsson, J. Nedergaard, and B. Cannon Thermogenic Responses in Brown Fat Cells Are Fully UCP1-dependent. UCP2 OR UCP3 DO NOT SUBSTITUTE FOR UCP1 IN ADRENERGICALLY OR FATTY ACID-INDUCED THERMOGENESIS J. Biol. Chem., August 11, 2000; 275(33): 25073 - 25081. [Abstract] [Full Text] [PDF]
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B. M. Jucker, J. Ren, S. Dufour, X. Cao, S. F. Previs, K. S. Cadman, and G. I. Shulman 13C/31P NMR Assessment of Mitochondrial Energy Coupling in Skeletal Muscle of Awake Fed and Fasted Rats. RELATIONSHIP WITH UNCOUPLING PROTEIN 3 EXPRESSION J. Biol. Chem., December 8, 2000; 275(50): 39279 - 39286. [Abstract] [Full Text] [PDF]
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C. Huppertz, B. M. Fischer, Y.-B. Kim, K. Kotani, A. Vidal-Puig, L. J. Slieker, K. W. Sloop, B. B. Lowell, and B. B. Kahn Uncoupling Protein 3 (UCP3) Stimulates Glucose Uptake in Muscle Cells through a Phosphoinositide 3-Kinase-dependent Mechanism J. Biol. Chem., April 13, 2001; 276(16): 12520 - 12529. [Abstract] [Full Text] [PDF]
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L. de Meis Uncoupled ATPase Activity and Heat Production by the Sarcoplasmic Reticulum Ca2+-ATPase. REGULATION BY ADP J. Biol. Chem., June 29, 2001; 276(27): 25078 - 25087. [Abstract] [Full Text] [PDF]
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S. Cadenas, K. S. Echtay, J. A. Harper, M. B. Jekabsons, J. A. Buckingham, E. Grau, A. Abuin, H. Chapman, J. C. Clapham, and M. D. Brand The Basal Proton Conductance of Skeletal Muscle Mitochondria from Transgenic Mice Overexpressing or Lacking Uncoupling Protein-3 J. Biol. Chem., January 18, 2002; 277(4): 2773 - 2778. [Abstract] [Full Text] [PDF]
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D.-W. Gong, S. Monemdjou, O. Gavrilova, L. R. Leon, B. Marcus-Samuels, C. J. Chou, C. Everett, L. P. Kozak, C. Li, C. Deng, et al. Lack of Obesity and Normal Response to Fasting and Thyroid Hormone in Mice Lacking Uncoupling Protein-3 J. Biol. Chem., May 19, 2000; 275(21): 16251 - 16257. [Abstract] [Full Text] [PDF]
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