Departments of 1 Physiology, 2 Health and Exercise Science, and 3 Food Science and Human Nutrition, Colorado State University, Fort Collins 80523; 4 Center for Human Nutrition, University of Colorado Health Science Center, Denver, Colorado 80262; and 5 Eli Lilly Corporation, Lilly Corporate Center, Indianapolis, Indiana 46285
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This cross-sectional
investigation sought to determine the relationship between selected
metabolic, endocrine, and anthropometric factors and skeletal muscle
UCP3 mRNA in healthy adult humans. Twenty-four healthy adults (13 male
and 11 female) across a range of aerobic capacity, age, and body
composition were studied. Muscle biopsies were obtained from the vastus
lateralis, from which UCP3 mRNA was quantified by Northern blot, and
fiber type was determined by use of the myosin ATPase staining
procedure. In addition, resting energy expenditure and maximum rate of
oxygen consumption were determined by indirect calorimetry, body
composition was determined by dual-energy X-ray absorptiometry, and
fasting plasma leptin and insulin were determined by ELISA. UCP3 mRNA
was correlated positively with the percent type I fibers
(r = 0.842, P < 0.001), plasma leptin
(r = 0.454, P = 0.026), and plasma
insulin (r = 0.615, P < 0.001) and
inversely to age (r = 0.411, P = 0.046). Stepwise multiple regression analysis determined that percent type I muscle fibers was the best predictor of vastus lateralis UCP3
mRNA, and no other variable entered the equation (model
r2 = 0.66). This study suggests that of the
variables measured, UCP3 mRNA is primarily related to skeletal muscle
fiber type in healthy adults. The factors that contribute to
fiber-specific differences in UCP3 mRNA expression will need to be
examined in future studies.
uncoupling proteins; leptin; metabolic rate
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE FACTOR(S) THAT CONTRIBUTE to the interindividual variability in resting metabolic rate have been the subject of intense research interest (38, 44, 54). The recent cloning of novel uncoupling protein isoforms (UCP2 and UCP3) has stimulated interest in potential molecular mediators of the variability in metabolic rate and susceptibility to obesity (8, 13, 15). The canonical UCP isoform (UCP1) is well accepted to act as an uncoupler of electron transport and oxidative phosphorylation in brown adipose tissue (BAT), resulting in the regulated production of heat (11, 25). In contrast, there is considerable debate about whether the novel UCPs are truly uncouplers in vivo, and the specific physiological role of UCP2 and UCP3 in skeletal muscle remains to be elucidated (33). There is evidence indicating that UCP2 and UCP3 function similarly to UCP1 in dissipating the proton gradient of the inner mitochondrial membrane during oxidative respiration (8, 13, 15, 17). It is intuitive then to investigate the relationship between the expression of these novel proteins and other variables known to be associated with metabolism.
Studies aimed at understanding the regulation of UCP3 gene expression have demonstrated tissue-specific responses to perturbations designed or "hypothesized" to alter UCP3 gene regulation. The expression and regulation of UCP3 in skeletal muscle are of considerable interest because of the large mass of this organ and its well-documented contribution to both basal metabolism (40) and basal proton leak (39). UCP2 is speculated to function similarly to UCP3; however, the specific importance of UCP2 in skeletal muscle is questionable. Previous reports indicate low levels of UCP2 mRNA in rodent skeletal muscle, although ubiquitously distributed among tissues (7, 13, 17), and a recent report by Pecqueur et al. (34) revealed that there was no UCP2 in human skeletal muscle. UCP3 has a long (UCP3L) and a short (UCP3S) mRNA transcript; however, evidence indicates an approximately equal distribution of the two transcripts (43). For example, Schrauwen et al. (43) report a strong correlation between the expression of UCP3L and that of UCP3S (r = 0.83, P < 0.0005) and demonstrate that they respond to perturbations in a similar manner. Therefore, it is prudent to measure only total UCP3 mRNA content in skeletal muscle.
This study sought to determine the metabolic, endocrine, and anthropometric factors that are related to UCP3 gene expression in skeletal muscle from healthy adult humans.
![]() |
SUBJECTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects. After approval from the Colorado State University Human Subjects Committee, this study was performed on 24 healthy adults (N = 13 males, 11 females) aged 20-48 yr. Exclusion criteria included any disease, condition, or drug that could affect metabolic rate. Smokers and habitual alcohol consumers were not permitted to participate.
Study protocol. Subjects were instructed to report to the Human Performance Clinical Research Laboratory (HPCRL) on four separate occasions within a 2-wk time period. The subjects were urged not to change their lifestyle during their participation in the study with the exception of short-term fasting and limited activity before and after specific protocols.
Resting energy expenditure. Resting energy expenditure (REE) was measured after a 12-h fast and 48 h without regular exercise. Subjects were instructed to report to the HPCRL in the morning after a normal night of sleep. Energy expenditure was then assessed using the SensorMedics VMAX ventilated hood indirect calorimeter (SensorMedics, Yorba Linda, CA). The subjects were tested in the supine position in a darkened, thermoneutral room under a clear plastic hood. Subjects were also supplied with foam earplugs to reduce any auditory stimuli. The subjects were instructed to refrain from performing any limb movements through the duration of the assessment. Measurements were taken for 60-90 min, depending on the time required to reach and maintain a metabolic steady state. Carbon dioxide and oxygen volumes of the last 30 min of each assessment were averaged, converted to kilocalories using the Weir equation (53), and expressed on a per minute basis. Estimated fat and carbohydrate oxidation rates were calculated on the basis of the average respiratory exchange ratio of the final 30 min of the measurement period using the caloric equivalents of Livesey and Elia (28).
Plasma leptin and insulin concentrations.
Immediately after the measurement of REE, blood samples were taken from
an antecubital vein. Samples were stored at 80°C until processing.
Plasma leptin and insulin levels were determined in duplicate by ELISA
(Diagnostic Systems Labs, Dallas, TX).
Aerobic fitness.
Maximal oxygen consumption (O2 max) was
determined using the Modified Balke Multistage Progressive treadmill
protocol, in which the slope of the treadmill (Quinton model no. 24-72, Bothell, WA) was increased by 1% per minute while the speed remained constant (1). Oxygen consumption and carbon dioxide
production were measured using the open-circuit indirect calorimetry
system of the SensorMedics 2900 metabolic measurement chart
(SensorMedics, Yorba Linda, CA) at rest, during exercise, and during
recovery from exercise. An individual's
O2 max was calculated by averaging the
highest three values of oxygen consumption during the test.
Muscle biopsy.
A muscle biopsy was taken from the vastus lateralis under local
anesthesia. Subjects were instructed not to exercise for 48 h
before the biopsy. Fifty to one hundred milligrams of tissue were
harvested and separated for assay and slide preparation. The aliquot
saved for assay was immediately frozen in liquid nitrogen and stored at
80°C until analysis. The remainder of the sample was suspended and
frozen in a gum tragacanth medium and stored at
80°C for
histochemical analysis.
UCP3 mRNA and histochemical analysis.
The RNA for UCP3 was isolated from the biopsy samples via the methods
of Chomczynski and Sacchi (12). RNA from human muscle was
isolated using TRIZOL (Life Technologies, Rockville, MD) as described
in the manufacturer's instructions. Fifteen micrograms of sample RNA
were size fractionated on a 1.5% agarose gel containing 0.66 M
formaldehyde, and the integrity of the RNA was verified by observation
of the 16 and 18S ribosomal bands under ultraviolet light. The RNA was
transferred to Nytran membranes by use of the Turboblotter system
(Schleicher and Schuell, Keene, NH), following the manufacturer's
instructions. The blots were prehybridized for 1 h at 42°C in
Ultrahyb (Ambion, Austin, TX). The blots were then hybridized overnight
at 42°C in fresh hybridization solution containing 1 × 106 counts · min1
(cpm) · ml
1 of a [
-32P]CTP
(3,000 Ci/mmol; New England Nuclear, Boston, MA)-random primed labeled
full-length UCP3 cDNA. The cDNA probe was generated from cloned human
UCP3 by PCR and was labeled using the random primers labeling system
(Life Technologies, Rockville, MD). The filters were washed 2 × 5 min in 1× sodium chloride-sodium citrate (SSC)-0.5% SDS at
42°C and for 2 × 15 min in 0.1× SSC-0.5% SDS at 42°C. Blots
were visualized by phosphorimaging and quantified with the use of
Imagequant software (Molecular Dynamics, Sunnyvale, CA). After
quantification for UCP3 mRNA, blots were stripped and reprobed for
actin mRNA using the full-length actin cDNA that was labeled with
[
-32P]CTP using the random primers labeling system
(Life Technologies). All UCP3 signals were normalized to the actin
signal to account for unequal loading of RNA.
Body composition. Total body mass was measured to 0.1 kg and body height to the nearest centimeter on a physician's balance scale (Detecto, Webb City, MO). Body mass index (BMI) was calculated from body weight and height (kg/m2). A DPX-IQ full-size densitometer was used to determine body density (Lunar, Madison, WI). Subjects were asked to not eat for 4 h before the dual-energy X-ray absorptiometry (DEXA) scan. The assessment required subjects to remove all metal articles and lie flat in a supine position on the DEXA table. The speed of the scan was determined by the thickness of the subject's chest. The variables determined by each scan include percent body fat, fat-free mass (in kg), and lean body mass (in kg).
Statistics.
All statistical procedures were performed with Statistical Package for
the Social Sciences (SPSS) 10.0. Means and standard deviations were
calculated and are reported in Table
1. Student's t-tests
were performed to compare means between genders; this is also shown in
Table 1. Pearson correlations were performed for all variables. The
level of statistical significance was set at P 0.05. Partial correlations were performed to control for the variables of
body mass and fat mass. Stepwise regression analysis was employed to
determine the best prediction model of UCP3 mRNA expression.
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Table 1 presents selected anthropometric and metabolic
characteristics of the population sample. The data presented include the mean and standard deviation and minimum and maximum data points for
each variable. Table 2 presents selected
Pearson R correlations of interest.
|
UCP3 mRNA.
UCP3 mRNA was not related to resting rate of oxygen consumption
(O2; r =
0.091,
P = 0.672) or REE (r =
0.175,
P = 0.415) but was related to plasma leptin
(r = 0.454, P = 0.026; Fig.
1A), percentage of type I
fiber (%type I fiber; r = 0.842, P < 0.001; Fig. 1B), age
(r =
0.411, P = 0.046; Fig.
1C), and plasma insulin (r = 0.615, P = 0.001; Fig. 1D). Only two of the
correlations remained significant when male and female subjects were
analyzed separately. The relationship between UCP3 mRNA and %type I
fiber remained significant for both genders [male (M):
r = 0.893, P < 0.001; female (F):
r = 0.805, P = 0.003], and the
relationship between UCP3 mRNA and plasma insulin remained significant
for females (M: r = 0.181, P = 0.554;
F: r = 0.774, P = 0.005). For males,
UCP3 mRNA was not related to resting
O2
(r = 0.130, P = 0.671), REE
(r = 0.021, P = 0.947), leptin
(r = 0.219, P = 0.473), or age
(r =
0.295, P = 0.328). For females,
UCP3 mRNA was also not related to resting
O2 (r = 0.414, P = 0.205), REE (r = 0.371, P = 0.262), leptin (r = 0.449, P = 0.166), and age (r =
0.443, P = 0.172). Step-wise multiple regression was performed
to determine the best prediction model of UCP3 mRNA. The %type I
fibers was the best predictor of UCP3 mRNA (r = 0.809, P < 0.01) and was the only variable to fit
into the model.
|
REE and resting O2.
In this data set, REE (kJ/min) was related to lean body mass
(r = 0.871, P < 0.001), body mass
(r = 0.807, P < 0.001), body fat
percentage (r =
0.419, P = 0.042),
and body surface area (r = 0.807, P < 0.001). Resting
O2 was also related to
lean body mass (r = 0.744, P < 0.001),
body mass (r = 0.578, P = 0.003), and
body surface area (r = 0.585, P = 0.003).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The primary finding from the present study is that there are
significant relationships between UCP3 mRNA and plasma leptin concentration, plasma insulin concentration, %type I fiber, and age.
Also of importance is that no relationship was found between REE or
O2 max and UCP3 mRNA.
Fiber type-UCP3 mRNA relationship. The first account regarding UCP3, by Boss et al. (8), reported mRNA to be highest in rodent skeletal muscle. More specifically, UCP3 mRNA was highest in tensor fascia latae (fast-twitch glycolytic), tibialis anterior (fast-twitch oxidative-glycolytic), and gastrocnemius (mixed) muscles and lower in soleus muscle (slow-twitch oxidative). More recently Hesselink et al. (20) developed and utilized a UCP3-specific antibody in an immunohistochemical procedure to show that UCP3 protein levels are expressed most abundantly in type IIb, second in type IIa, and lowest in type I human skeletal muscle fibers. Thus work both in rodents and the single report in humans suggests that UCP3 mRNA (rodents) or protein (human) expression is higher in fast twitch fibers.
Our results, however, show a significant positive relationship between skeletal muscle UCP3 mRNA and the percentage of type I skeletal muscle fibers (r = 0.842, P < 0.001). Although our data are in agreement with expected fiber type differences in mitochondrial density, i.e., highest mitochondrial density in type I fibers (41), it is clear from the available work in this area that neither UCP3 mRNA nor the corresponding protein content is necessarily a simple marker for mitochondrial density (8, 20). Given the prior observations that UCP3 protein content is higher in type II muscle in humans (20), it must be argued that transcriptional and translational control of UCP3 is complex. Considerable additional work must be done to characterize those factors that contribute to changes in both UCP3 mRNA and the expression of the mature protein. A major advantage in the work of Hesselink et al. (20) is that these authors utilized an immunohistochemical technique to measure UCP3 protein in cross sections that were serially stained to determine fiber type. In contrast, the present study measured gene expression (steady-state UCP3 mRNA) from whole muscle homogenates and determined fiber type on cross sections from the same tissue sample. Thus differences in methodology make straightforward comparisons to the work of Hesselink et al. difficult. It is possible that both transcription and translation rates for UCP3 are not uniform between fiber types (i.e., despite lower mRNA levels in type II skeletal muscle, this tissue translates more efficiently than type I skeletal muscle). Giacobino (14) described a series of studies in which the amplitude of UCP3 mRNA changes in response to fasting was less robust than the corresponding change in UCP3 protein. Sivitz et al. (47) demonstrated UCP3 mRNA and protein changing concomitantly in rodent skeletal muscle but strongly suggested that both transcriptional and translational regulation of UCPs may be isoform, tissue, species, and perturbation specific. In addition to differences in the methodological approach utilized, it must be noted that Hesselink et al. (20) studied only 3 healthy and 10 type II diabetic men, whereas the present study included both genders, all of good health. We performed a partial correlation controlling for gender and found that UCP3 mRNA and percentage of type I fibers remained statistically significant (r = 0.84). The correlations between UCP3 mRNA and percentage of type I fibers for males and females were r = 0.893 (P = 0.001) and r = 0.805 (P = 0.003), respectively. As noted earlier, there was no statistical difference between men and women regarding UCP3 mRNA or percentage of type I fibers. Several putative roles for UCP3, in addition to decreasing the mitochondrial protonmotive force, have been proposed (18, 29). One proposed function of UCP3 is the reduction of reactive oxygen species (ROS) (19, 21, 50). Intracellular ROS are generated as byproducts of cellular metabolism. Imbalanced cellular redox status is a potent pathogenic factor that leads to various degenerative diseases (52). Fiber type differences in ROS formation are not well understood, although recent work (27) has provided some evidence of increased accumulation of markers of oxidative stress in type I muscle. More research on this specific topic must be carried out before any formal conclusions can be made. In addition to the potential function in defense of ROS accumulation, both Himms-Hagen and Harper (22) and Schrauwen et al. (42) have recently suggested that UCP3 may act to protect the mitochondria against accumulation of nonesterified fatty acids (NEFA) by translocating fatty acids outward from the mitochondrial matrix. Prior research has shown that red muscle has a higher capacity for protein-mediated fatty acid transport into the mitochondria (5, 24), suggesting that type I or red muscle fibers may have a greater need for removing excess NEFA. In the context of the proposed function of UCP3 in the outward transport of NEFA, the higher expression of UCP3 observed in type I fibers in the present study might be an adaptive response. A recent report by Moore et al. (31) revealed that mitochondrial thioesterase (MTE)-1 mRNA expression is increased in skeletal muscle of transgenic mice overexpressing UCP3, which also supports the hypothesis of UCP3 as a fatty acid exporter. Nevertheless, more research is needed to explicate the role of UCP3 in skeletal muscle.Plasma leptin and insulin concentrations. The hormone leptin is produced primarily in adipose tissue and is the protein product of the ob gene. Leptin has been shown to act on several peripheral target tissues (3, 32, 45), but the majority of leptin action appears to occur in the hypothalamus, where it acts to decrease food consumption and presumably increase energy dissipation (23). However, research has shown that leptin treatment to ob/ob mice (lack of functional leptin) causes an increase in muscular UCP3 mRNA expression (16, 17), indicating that leptin can regulate UCP3 gene expression. The results of this study are in agreement with the previously observed relationship between plasma leptin levels and UCP3 mRNA levels in skeletal muscle. Note that we did not find a relationship between UCP3 mRNA expression and body fat percentage in this study; however, Bao et al. (2) have shown a positive correlation of skeletal muscle UCP3 mRNA with body fat percentage and BMI in nondiabetic individuals. A potential explanation for the absence of this relationship within the current data is that this sample is relatively lean. The average body fat percentages of subjects in the study conducted by Bao et al. were considerably higher (26.2 ± 2.9, 28.5 ± 2.6, and 31.2 ± 2.9%) than the percentage of the present study (21.5 ± 9.8%). It is possible that the relationship between UCP3 mRNA and body fat percentage observed by Bao et al. is only observed at higher body fat levels. Although the females studied had a comparable body fat percentage (29.6 ± 7.0%), this relationship was not significant. Other confounding factors not examined in this study may have influenced this relationship.
Boivin et al. (4) found no evidence of a significant relationship between skeletal muscle expression of UCP3 and fasting plasma insulin concentrations in 18 healthy males. In contrast, the present data present a robust relationship between these parameters (r = 0.615, P = 0.001). When separated for the effect of gender, the UCP3 mRNA and plasma insulin relationship remained significant only in the females (r = 0.774, P = 0.005). Thus our data agree with those of Boivin et al. regarding the UCP3 mRNA-insulin relationships in healthy males but suggest that this relationship is gender dependent.Age. Older individuals have often been characterized by lower REE (10, 37, 46, 48, 49). The age-related decline in REE is also associated with increased body weight and fatness, decreased physical activity (37, 48, 49), decreased energy intake (30), and decreased lean body mass (35, 36). In the context of proposed functions of UCP3, the age-related decline in REE may, in part, be a function of a concomitant reduction in UCP3-mediated uncoupling. Interestingly, while the present study does suggest that UCP3 decreases with age, UCP3 mRNA was unrelated to REE. Thus functions for UCP3 other than thermogenesis must be considered. The decline of UCP3 mRNA with age may be important in explaining the increased prevalence of other degenerative diseases with age. As stated previously, UCP3 may function to reduce the accumulation of ROS resulting from fatty acid oxidation. If UCP3 levels are declining with age, this may explain the means by which ROS levels are elevated and subsequently cause degenerative diseases (26, 51, 52). Clearly, additional work must be done to clarify what role, if any, UCP3 might play in skeletal muscle ROS accumulation. Furthermore, our data only include men and women between the ages of 18 and 50 yr, a relatively young sample. Additional research must be performed to investigate the relationships between UCP3, ROS, and aging in an older population sample.
In conclusion, we analyzed metabolic and anthropometric variables of 24 men and women, aged 20-48 yr, to identify the relationship between these variables and UCP3 gene expression in skeletal muscle. Our results indicated that skeletal muscle UCP3 mRNA is directly associated with plasma leptin concentration, plasma insulin concentration, and percentage of type I skeletal muscle fibers and inversely related to age. Additional research must be done to further elucidate the relationship between these factors and the role of UCP3 in skeletal muscle fatty acid metabolism and ROS accumulation. ![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: M. Hickey, Colorado State Univ., Dept. of Health and Exercise Science, B215A Moby Complex, Fort Collins, CO 80523 (E-mail: hickey{at}cahs.colostate.edu).
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.
June 18, 2002;10.1152/ajpendo.00449.2001
Received 5 October 2001; accepted in final form 12 June 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Balke, B,
and
Ware RW.
An experimental study of "physical fitness" of Air Force personnel.
US Armed Forces Medical Journal
10:
675-688,
1959.
2.
Bao, S,
Kennedy A,
Wojciechowski B,
Wallace P,
Ganaway E,
and
Garvey WT.
Expression of mRNAs encoding uncoupling proteins in human skeletal muscle: effects of obesity and diabetes.
Diabetes
47:
1935-1940,
1998[Abstract].
3.
Berti, L,
Kellerer M,
Capp E,
and
Haring HU.
Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect.
Diabetologia
40:
606-609,
1997[ISI][Medline].
4.
Boivin, M,
Camirand A,
Carli F,
Hoffer LJ,
and
Silva JE.
Uncoupling protein-2 and -3 messenger ribonucleic acids in adipose tissue and skeletal muscle of healthy males: variability, factors affecting expression, and relation to measures of metabolic rate.
J Clin Endocrinol Metab
85:
1975-1983,
2000
5.
Bonen, A,
Luiken JJ,
Liu S,
Dyck DJ,
Kiens B,
Kristiansen S,
Turcotte LP,
van der Vusse GJ,
and
Glatz JF.
Palmitate transport and fatty acid transporters in red and white muscles.
Am J Physiol Endocrinol Metab
275:
E471-E478,
1998
6.
Borg, GA.
Psychological bases of perceived exertion.
Med Sci Sports Exerc
14:
377-381,
1982[ISI][Medline].
7.
Boss, O,
Samec S,
Dulloo A,
Seydoux J,
Muzzin P,
and
Giacobino JP.
Tissue-dependent upregulation of rat uncoupling protein-2 expression in response to fasting or cold.
FEBS Lett
412:
111-114,
1997[ISI][Medline].
8.
Boss, O,
Samec S,
Paoloni-Giacobino A,
Rossier C,
Dulloo A,
Seydoux J,
Muzzin P,
and
Giacobino JP.
Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression.
FEBS Lett
408:
39-42,
1997[ISI][Medline].
9.
Brooke, MH,
and
Kaiser KK.
Three "myosin adenosine triphosphatase" systems: the nature of their pH lability and sulfhydryl dependence.
J Histochem Cytochem
18:
670-672,
1970[ISI][Medline].
10.
Calloway, DH,
and
Zanni E.
Energy requirements and energy expenditure of elderly men.
Am J Clin Nutr
33:
2088-2092,
1980[Abstract].
11.
Cannon, B,
Matthias A,
Golozoubova V,
Ohlson KBE,
Andersson U,
Jacobsson A,
and
Nedergaard J.
Unifying and distinguishing features of brown and white adipose tissues: UCP1 vs. other UCPs.
In: Progress in Obesity Research, edited by Ailhaud G,
and Guy-Grands B.. London: John Libby, 1999, p. 13-26.
12.
Chomczynski, P,
and
Sacchi N.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
Anal Biochem
162:
156-159,
1987[ISI][Medline].
13.
Fleury, C,
Neverova M,
Collins S,
Raimbault S,
Champigny O,
Levi-Meyrueis C,
Bouillaud F,
Seldin MF,
Surwit RS,
Ricquier D,
and
Warden CH.
Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia.
Nat Genet
15:
269-272,
1997[ISI][Medline].
14.
Giacobino, JP.
Uncoupling protein 3 biological activity.
Biochem Soc Trans
29:
774-777,
2001[ISI][Medline].
15.
Gimeno, RE,
Dembski M,
Weng X,
Deng N,
Shyjan AW,
Gimeno CJ,
Iris F,
Ellis SJ,
Woolf EA,
and
Tartaglia LA.
Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis.
Diabetes
46:
900-906,
1997[Abstract].
16.
Gomez-Ambrosi, J,
Fruhbeck G,
and
Martinez JA.
Leptin, but not a 3-adrenergic agonist, upregulates muscle uncoupling protein-3 messenger RNA expression: short-term thermogenic interactions.
Cell Mol Life Sci
55:
992-997,
1999[ISI][Medline].
17.
Gong, DW,
He Y,
Karas M,
and
Reitman M.
Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, 3-adrenergic agonists, and leptin.
J Biol Chem
272:
24129-24132,
1997
18.
Harper, ME,
Dent RM,
Bezaire V,
Antoniou A,
Gauthier A,
Monemdjou S,
and
McPherson R.
UCP3 and its putative function: consistencies and controversies.
Biochem Soc Trans
29:
768-773,
2001[ISI][Medline].
19.
Harper, ME,
and
Himms-Hagen J.
Mitochondrial efficiency: lessons learned from transgenic mice.
Biochim Biophys Acta
1504:
159-172,
2001[ISI][Medline].
20.
Hesselink, MK,
Keizer HA,
Borghouts LB,
Schaart G,
Kornips CF,
Slieker LJ,
Sloop KW,
Saris WH,
and
Schrauwen P.
Protein expression of UCP3 differs between human type 1, type 2a, and type 2b fibers.
FASEB J
15:
1071-1073,
2001
21.
Himms-Hagen, J,
and
Harper ME.
Biochemical aspects of the uncoupling proteins: view from the chair.
Int Int J Obes Relat Metab Disord
23, Suppl 6:
S30-S32,
1999.
22.
Himms-Hagen, J,
and
Harper ME.
Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis.
Exp Biol Med (Maywood)
226:
78-84,
2001
23.
Hynes, GR,
and
Jones PJ.
Leptin and its role in lipid metabolism.
Curr Opin Lipidol
12:
321-327,
2001[ISI][Medline].
24.
Kempen, KP,
Saris WH,
Kuipers H,
Glatz JF,
and
Van Der Vusse GJ.
Skeletal muscle metabolic characteristics before and after energy restriction in human obesity: fibre type, enzymatic beta-oxidative capacity and fatty acid-binding protein content.
Eur J Clin Invest
28:
1030-1037,
1998[ISI][Medline].
25.
Klingenberg, M.
Mechanism and evolution of the uncoupling protein of brown adipose tissue.
Trends Biochem Sci
15:
108-112,
1990[ISI][Medline].
26.
Lehucher-Michel, MP,
Lesgards JF,
Delubac O,
Stocker P,
Durand P,
and
Prost M.
Oxidative stress and human disease. Current knowledge and perspectives for prevention.
Presse Med
30:
1076-1081,
2001[ISI][Medline].
27.
Liu, J,
Yeo HC,
Overvik-Douki E,
Hagen T,
Doniger SJ,
Chu DW,
Brooks GA,
and
Ames BN.
Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants.
J Appl Physiol
89:
21-28,
2000
28.
Livesey, G,
and
Elia M.
Estimation of energy expenditure, net carbohydrate utilization, and net fat oxidation and synthesis by indirect calorimetry: evaluation of errors with special reference to the detailed composition of fuels.
Am J Clin Nutr
47:
608-628,
1988[Abstract].
29.
Lowell, BB.
Uncoupling protein-3 (UCP3): a mitochondrial carrier in search of a function.
Int J Obes Relat Metab Disord
23, Suppl 6:
S43-S45,
1999[Medline].
30.
McGandy, RB,
Barrows CH, Jr.,
Spanias A,
Meredith A,
Stone JL,
and
Norris AH.
Nutrient intakes and energy expenditure in men of different ages.
J Gerontol
21:
581-587,
1966[ISI][Medline].
31.
Moore, GB,
Himms-Hagen J,
Harper ME,
and
Clapham JC.
Overexpression of UCP-3 in skeletal muscle of mice results in increased expression of mitochondrial thioesterase mRNA.
Biochem Biophys Res Commun
283:
785-790,
2001[ISI][Medline].
32.
Muller, G,
Ertl J,
Gerl M,
and
Preibisch G.
Leptin impairs metabolic actions of insulin in isolated rat adipocytes.
J Biol Chem
272:
10585-10593,
1997
33.
Muzzin, P,
Boss O,
and
Giacobino JP.
Uncoupling protein 3: its possible biological role and mode of regulation in rodents and humans.
J Bioenerg Biomembr
31:
467-473,
1999[ISI][Medline].
34.
Pecqueur, C,
Alves-Guerra MC,
Gelly C,
Levi-Meyrueis C,
Couplan E,
Collins S,
Ricquier D,
Bouillaud F,
and
Miroux B.
Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation.
J Biol Chem
276:
8705-8712,
2001
35.
Piers, LS,
Soares MJ,
McCormack LM,
and
O'Dea K.
Is there evidence for an age-related reduction in metabolic rate?
J Appl Physiol
85:
2196-2204,
1998
36.
Poehlman, ET,
Berke EM,
Joseph JR,
Gardner AW,
Katzman-Rooks SM,
and
Goran MI.
Influence of aerobic capacity, body composition, and thyroid hormones on the age-related decline in resting metabolic rate.
Metabolism
41:
915-921,
1992[ISI][Medline].
37.
Poehlman, ET,
Melby CL,
and
Badylak SF.
Relation of age and physical exercise status on metabolic rate in younger and older healthy men.
J Gerontol B Psychol Sci Soc Sci
46:
B54-B58,
1991.
38.
Ravussin, E,
and
Gautier JF.
Metabolic predictors of weight gain.
Int J Obes Relat Metab Disord
23, Suppl 1:
37-41,
1999[Medline].
39.
Rolfe, DF,
and
Brand MD.
Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate.
Am J Physiol Cell Physiol
271:
C1380-C1389,
1996
40.
Rolfe, DF,
Newman JM,
Buckingham JA,
Clark MG,
and
Brand MD.
Contribution of mitochondrial proton leak to respiration rate in working skeletal muscle and liver and to SMR.
Am J Physiol Cell Physiol
276:
C692-C699,
1999
41.
Saltin, B,
and
Gollnick PD.
Skeletal muscle adaptability: significant for metablism and performance.
In: Handbook of Physiology. Skeletal Muscle. Bethesda, MD: Am Physiol Soc, 1983, sect. 10, chapt. 19, p. 555-632.
42.
Schrauwen, P,
Saris WH,
and
Hesselink MK.
An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix.
FASEB J
15:
2497-2502,
2001
43.
Schrauwen, P,
Schaart G,
Saris WH,
Slieker LJ,
Glatz JF,
Vidal H,
and
Blaak EE.
The effect of weight reduction on skeletal muscle UCP2 and UCP3 mRNA expression and UCP3 protein content in type II diabetic subjects.
Diabetologia
43:
1408-1416,
2000[ISI][Medline].
44.
Schrauwen, P,
Walder K,
and
Ravussin E.
Human uncoupling proteins and obesity.
Obes Res
7:
97-105,
1999[Abstract].
45.
Shimabukuro, M,
Koyama K,
Chen G,
Wang MY,
Trieu F,
Lee Y,
Newgard CB,
and
Unger RH.
Direct antidiabetic effect of leptin through triglyceride depletion of tissues.
Proc Natl Acad Sci USA
94:
4637-4641,
1997
46.
Shock, NW,
Watkin DM,
Yiengst JM,
Norris AH,
Gaffney GW,
Gregerman RI,
and
Falzone JA.
Age differences in the water content of the body as related to basal oxygen consumption in males.
J Gerontol
18:
1-8,
1963[ISI].
47.
Sivitz, WI,
Fink BD,
and
Donohoue PA.
Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression.
Endocrinology
140:
1511-1519,
1999
48.
Van Pelt, RE,
Jones PP,
Davy KP,
Desouza CA,
Tanaka H,
Davy BM,
and
Seals DR.
Regular exercise and the age-related decline in resting metabolic rate in women.
J Clin Endocrinol Metab
82:
3208-3212,
1997
49.
Vaughan, L,
Zurlo F,
and
Ravussin E.
Aging and energy expenditure.
Am J Clin Nutr
53:
821-825,
1991[Abstract].
50.
Vidal-Puig, AJ,
Grujic D,
Zhang CY,
Hagen T,
Boss O,
Ido Y,
Szczepanik A,
Wade J,
Mootha V,
Cortright R,
Muoio DM,
and
Lowell BB.
Energy metabolism in uncoupling protein 3 gene knockout mice.
J Biol Chem
275:
16258-16266,
2000
51.
Wei, YH.
Oxidative stress and mitochondrial DNA mutations in human aging.
Proc Soc Exp Biol Med
217:
53-63,
1998[Abstract].
52.
Wei, YH,
Lu CY,
Wei CY,
Ma YS,
and
Lee HC.
Oxidative stress in human aging and mitochondrial disease: consequences of defective mitochondrial respiration and impaired antioxidant enzyme system.
Chin J Physiol
44:
1-11,
2001[ISI][Medline].
53.
Weir, JB.
A new method for calculating metabolic rate with special reference to protein metabolism.
J Physiol
109:
1-9,
1949[ISI].
54.
Weyer, C,
Snitker S,
Rising R,
Bogardus C,
and
Ravussin E.
Determinants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects.
Int J Obes Relat Metab Disord
23:
715-722,
1999[Medline].
|
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |