| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; and 2 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs.
brown adipose tissue; white adipose tissue; basal metabolic rate; reactive oxygen species
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
AT THE LEVEL OF the whole body, energy expenditure represents the sum total of the energy costs associated with obligatory and facultative metabolic processes. Energy expenditure can be measured directly as heat production (thermogenesis) but is more commonly assessed indirectly as oxygen consumption. The former necessitates the use of a calorimeter and the latter an indirect calorimeter. During indirect calorimetry, carbon dioxide production is often measured simultaneously, allowing the calculation of respiratory quotients, which in turn allows the estimation of proportions of energy expenditure supported by dietary carbohydrate and fat.
Energy expenditure can be subdivided broadly into two categories of thermogenesis: obligatory and facultative. Obligatory thermogenic processes are essential for the life of all cells of the body and include those that support normal and consistent body temperatures (i.e., endothermy) (72). The largest component of obligatory thermogenesis is provided by the basal metabolic rate. Basal metabolic rate is measured in the resting and postabsorptive state and in a thermoneutral environment. Also considered an obligatory thermogenic process is the portion of diet-induced thermogenesis that results from the digestion, absorption, and metabolism of dietary nutrients. The most important of the endocrine factors governing obligatory thermogenesis are the thyroid hormones (131).
Although obligatory thermogenesis occurs continuously in all organs of the body, facultative thermogenesis can be rapidly switched on or off and occurs mainly in two tissues: skeletal muscle and brown adipose tissue (BAT). Energy expenditure attributable to exercise occurs mainly in skeletal muscle, with the addition of some concomitant energy substrate cycling in the liver. It is in skeletal muscle and BAT that heat is produced when endothermic organisms are in a cold environment. Shivering thermogenesis takes place in muscle, and nonshivering thermogenesis occurs in BAT. Although the acute activation of shivering and nonshivering thermogenic reactions does not require any change in the expression of thermogenic genes, chronic cold exposure invokes the expression of many genes that are important in thermoregulatory processes.
BAT thermogenesis is an important component of facultative
thermogenesis in many mammals, and its activity is regulated
principally by norepinephrine and the sympathetic nervous system
(72). In humans, BAT thermogenesis is important at birth
and in infancy. With age, however, BAT atrophies, and during adulthood
the amount of active tissue is normally small. In contrast, the
contribution of BAT thermogenesis to overall energy expenditure can be
very significant in rodents and many small mammals throughout their lives. This is evidenced by the approximate doubling of total body
energy expenditure after an acute dose of a 
3-adrenergic agonist in mice or rats (63, 138).
When total body energy expenditure is equal to the metabolizable energy from the diet (the energy substrates actually absorbed), a state of energy balance exists. Simply put, energy expenditure equals energy intake. The regulation of energy balance is extremely complex and very poorly understood. The fact that most of us remain in a state of energy balance for most of our lives is quite remarkable, considering the day-to-day intra- and interindividual variation in energy demands. The outcome of an extended period of negative energy balance (when expenditure exceeds intake) is undernutrition, which is characterized by loss of bodily energy stores, primarily adipose triglyceride. Similarly, the outcome of an extended period of positive energy balance is overnutrition, which is characterized by accretion of fat mass and obesity (89). Overnutrition is an increasingly common occurrence in affluent countries and in urban centers of many developing countries (54). The aim of this review is to examine possible roles of the uncoupling proteins (UCPs) in energy expenditure and thermoregulation.
| |
FROM "THERMOGENIN" TO THE IDENTIFICATION OF NOVEL UCPs |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
Uncoupling in BAT.
In most tissues most of the time, the oxidation of fuel
substrates results in mitochondrial ATP production through oxidative phosphorylation (118). Oxidative phosphorylation is driven
by the electrochemical gradient across the mitochondrial inner
membrane. As protons move down the electrochemical gradient and enter
the mitochondrial matrix through ATP synthase, the gradient is
dissipated. In BAT, the presence of uncoupling protein 1 (UCP1) allows
a unique alternative route of proton entry (99). Through
UCP1, protons bypass the ATP synthase route of entry and the energy of
the electrochemical gradient is dissipated as heat. As described above,
the heat production in BAT is essential for effective thermoregulation
in many small mammals and during human infancy, and its role in energy
balance and obesity has been described (70). During
uncoupling thermogenesis in BAT, the rate of heat production depends
on, and is limited by, the rate of substrate oxidation
(e.g., C16H32O2 + 23O2 
16CO2 + 16H2O + heat).
Mitochondrial proton conductance in tissues other than BAT. For just over a decade, it has been known that another sort of proton conductance occurs across the mitochondrial inner membrane in tissues other than BAT (3, 117). Accurate assessments of proton leak require simultaneous measurements of mitochondrial protonmotive force and oxygen consumption. In effect, it represents mitochondrial oxygen consumption when ATP synthesis (i.e., phosphorylation) is not occurring. Estimates of proton leak-dependent oxygen consumption in isolated rat liver cells and perfused rat skeletal muscle show that ~26% of resting energy expenditure is due to leak in liver cells (20, 23, 67, 101) and 52% in resting skeletal muscle (20, 117, 118). At the level of the whole body, it has been estimated that mitochondrial proton leak could account for ~15-20% of standard metabolic rate (118). The mechanism of proton leak is not well understood, although it has been thought that the UCP1 homologs are central to its mechanism. Recent findings however, suggest that these mitochondrial proton leak processes may be mediated primarily through other mechanisms (19, 25, 95). Several physiological functions have been proposed for proton leak: 1) heat production, 2) regulation of the efficiency of oxidative phosphorylation, 3) reduced production of reactive oxygen species (ROS) by mitochondria, and 4) a means to maintain the NAD+-to-NADH ratio sufficiently high to support carbon fluxes in biosynthetic processes (118).
Discovery of UCP1 homologs.
In recent years, four genes were discovered and classified as UCP1
homologs by virtue of their amino acid identity levels with the
prototypical UCP and on the basis of initial findings from their
heterologous expression in yeast: UCP2,
UCP3L/UCP3S (where L signifies the long
transcript and S the short transcript), UCP4, and UCP5/BMCP1 (2,
17, 53, 58, 90, 122). Inevitably, UCP was renamed "UCP1" to
distinguish it from its homologs. The question, however, remains as to
whether the UCP1 homologs have true thermogenic properties in vivo.
Experiments in yeast have frequently demonstrated that the UCP homologs
can decrease mitochondrial membrane potential (
), which is
consistent with, but certainly not conclusive of, uncoupling
(80). These approaches and findings have recently been
criticized for the possible erroneous interpretation of experimental
artifacts due to overexpression (137). Infrared imaging
has been used to evaluate the thermogenic properties of UCP2 in
cultured cells (107), but this method has not been
extended or duplicated with the other UCPs. Although it is well
accepted that fatty acids interact directly with UCP1, their role in
the activities of the novel UCPs is poorly understood (74,
134). Fatty acids activate UCP1 but are thought to be less
effective in the activation of UCP2 and UCP3 (114). The
latter may reflect true differences in the activation of uncoupling by
the homologs, or it may indicate that the homologs have other
physiological functions. Proton transport by UCP1 is dependent on a
histidine pair that is absent in the homologs, suggesting a complete
(UCP2) or partial (UCP3) inability in proton transport
(9). The recent discovery of UCP2 homologs in the carp and
the zebra fish (136), both of which are ectothermic
organisms (11), has further perplexed scientists.
Mitochondrial biogenesis of the UCPs.
The UCPs belong to a superfamily of proteins that includes the
oxoglutarate carrier (154) and the ADP/ATP carrier
proteins, each consisting of ~300 amino acids and all having similar
secondary structures (148). Like most mitochondrial
carrier proteins, UCPs are encoded by nuclear DNA and likely use
mechanisms of protein import similar to those described for yeast
proteins, i.e., the TIM and TOM systems (translocators of
the inner and outer mitochondrial membranes, respectively) (79,
91). The pathway of UCP1 import seems to involve the smaller
components of the mitochondrial intermembrane space for the direct
insertion of the UCPs into the inner mitochondrial membrane
where they are expected to dimerize (7, 86, 119, 151).
Experiments on the biogenesis of UCP1 have shown that the central
matrix loop drives import of the protein into the mitochondria (125). Little is known about the specific mechanisms
employed for the import of the other UCPs. However, a mutant human UCP3 variant (Arg70Trp, in the second matrix-facing loop), which was identified in our laboratory and showed no ability to alter in
yeast (21), failed to be imported into rat liver
mitochondria in an in organello import assay (unpublished observation).
Therefore, the matrix-facing loops in the UCPs could perhaps play a
significant role in the recognition and insertion of the proteins into
the inner mitochondrial membrane. Blue gel electrophoresis
experiments could advance our understanding of UCP import and confirm
the functional conformation of UCPs as dimers in the inner membrane.
| |
ANIMAL STUDIES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
Physiological and expression studies. Animal models have provided an excellent paradigm to analyze the possible physiological functions of UCPs. At the transcriptional level, mouse UCP1 (mUCP1) is regulated by adrenoreceptors (116) in brown adipocytes, whereas the promoter of mUCP2 was regulated by cAMP-dependent protein kinase in transiently transfected 3T3-L1 adipocytes (153). On the basis of the adipocytes' hypothesized function in adaptive thermogenesis, researchers have often exposed animals to cold as a method of examining UCP expression and possible function. Skeletal muscle rat UCP3 (rUCP3) increased up to threefold after a 6- to 24-h exposure to cold, whereas rUCP2 showed only a small increase, suggesting a role for only rUCP3 in thermoregulatory (shivering or other) mechanisms in muscle (132). In another study, however, skeletal muscle rUCP3 expression did not change with cold exposure but increased with 1 wk of fasting (14). Acute exercise resulted in significant increases of rUCP3, but not rUCP2, in white and red gastrocnemius muscles, whereas chronic exercise had no effect on either gene (39, 56). Endurance-trained rats, in contrast, had significantly decreased rUCP2 and rUCP3 expression in the tibialis anterior and soleus muscles and in the heart in the case of rUCP2; researchers (13) suggested a metabolic role for the UCPs in the rapid weight gain that sometimes occurs when exercise training ceases.
Importantly, the administration of FFAs to rats via intralipid plus heparin infusions caused significant increases in rUCP3, suggesting that FFAs may be an important mediator of the increase of rUCP3 in muscle during fasting (150). Streptozotocin administration increased levels of circulating FFAs and induced a 9.4-fold increase of rUCP3 but not rUCP2 in heart mRNA (68). In studies that used multiple muscle and adipocyte cell lines, peroxisome proliferator-activated receptors-
(PPAR-) agonists,
however, induced UCP2 expression (26, 135).
UCPs as regulators of the fuel substrate mix. The issue regarding whether UCP2 or UCP3 are mediators of thermogenesis or regulators of lipids as fuel substrates was recently raised. When the antilipolytic agent nicotinic acid was given to fed and fasted rats, there was a threefold increase in serum FFA and significantly increased rUCP2 and rUCP3 expression in muscle (120). The greatest increases occurred in the fast-twitch glycolytic gastrocnemius and tibialis anterior muscles rather than in the slow-twitch oxidative soleus muscle (120). These findings indicate a muscle-type dependency in the regulation of UCP2 and UCP3 expression and suggest a role in the regulation of fatty acid vs. glucose oxidation in muscle (120). In another experiment (121), the refeeding of isocaloric amounts of a low-fat diet in rats resulted in lower energy expenditure and lower mRNA levels of rUCP2 and rUCP3 mRNA in muscle, compared with ad libitum-fed control rats. This downregulation of rUCP2 and rUCP3 was abrogated by the refeeding of high-fat diets; in addition, regression analysis suggested that insulin resistance could explain the variability of rUCP2 and rUCP3 in muscle, emphasizing the possibility that UCPs may play a role in the regulation of lipids as fuel substrates (121). Furthermore, feeding a 45% high-fat diet for 8 wk resulted in a twofold increase of mUCP3, but not mUCP2, expression in skeletal muscle of obesity-prone but not obesity-resistant mouse strains (59). The increases of rUCP3 (and to a lesser extent rUCP2) in fasted rats were confirmed by a separate study (25); however, proton conductance was unchanged, suggesting that rUCP2 and rUCP3 might not be responsible for proton leak in skeletal muscle mitochondria. In ob/ob mice, mUCP2 mRNA levels in liver or white adipose tissue (WAT) were higher than in wild-type animals, but fasting did not increase mUCP2 expression (92). This multifaceted array of experiments in rodents advocates the possible important involvement of UCP2 and UCP3 in fuel substrate utilization (44).
Effects of leptin.
Leptin administration in rats resulted in a twofold increase of rUCP1
in BAT, a 62% increase of rUCP3 in BAT, and a twofold increase of
rUCP2 in epididymal WAT (123, 124). Leptin also increased
mUCP1 expression via the -adrenoreceptors (36), whereas it reduced adipose tissue via an mUCP1-dependent mechanism in BAT
(35). Further evidence for a role by leptin in the
regulation of UCP expression has come from adenoviral-mediated leptin
expression in ob/ob mice that resulted in mUCP3 and mUCP2
increases of expression in the muscle and pancreatic islets,
respectively (88). In other studies (48,
123), leptin administration induced rUCP2 and rUCP3 in a
nonsympathetic innervation pathway, whereas 3-adrenergic agonists also stimulated rUCP3. Leptin did not induce mUCP2 expression in either mouse epididymal WAT or mouse retroperitoneal WAT, but it
increased mUCP1 in retroperitoneal WAT and mUCP2 in epididymal WAT and
BAT, although this occurred in mUCP1 knockout mice only (35). mUCP2, on the other hand, did not differ between
lean and ob/ob mice in both epididymal WAT and
retroperitoneal WAT (37).
Transgenics and knockouts.
The deletion and/or overexpression of genes in animals are commonly
used to elucidate physiological functions of genes in whole organisms.
The interaction of such genetic interventions with altered
environmental conditions (e.g., diet) or with effects of
pharmaceuticals often assists in the identification of metabolic phenotypes. The knockout and transgenic animal models for UCP function
generated thus far are summarized in Table
1. mUCP1 knockout mice
(mUCP1
/) were nonobese and nonhyperphagic and did not
become obese when fed high-fat diets (49). However, the
animals were markedly cold sensitive (49), confirming the
important role that mUCP1 plays in cold-induced thermogenesis. Another
phenotype of the mUCP1/ mice was the higher
leak-dependent oxygen consumption rate in muscle (95), an
observation that may in part explain how these mice remain in energy
balance in the absence of UCP1 thermogenesis. However, the increased
proton leak in muscle of mUCP1/ mice was not
accompanied by any increase in the expression of UCP2 or UCP3.
Additional studies have shown that only UCP1 can mediate adaptive
nonshivering thermogenesis and that during prolonged thermogenic demand
there was no evidence for any UCP1-independent adaptive
nonshivering thermogenesis in muscle or any other organ (57). Finally, the ectopic expression of UCP1
(mUCP1/) in skeletal muscle results in resistance to
obesity, lower levels of glucose, insulin, and cholesterol, and
increased metabolic rates both at rest and with exercise
(87).
|
/
mice, and had normal responses to cold exposure and a high-fat diet
(6). These data strongly support the notion that mUCP2
does not have the same thermogenic properties as mUCP1. However,
mUCP2/ mice were quite resistant to
Tocoplasma gondii infection and had higher levels of ROS,
supporting a role for mUCP2 in ROS regulation (6).
Hepatocytes from ob/ob mice had increased mUCP2, relative to
lean mice, and mitochondria from ob/ob mice had an increased rate of proton leak and reduced ATP stores, which made them vulnerable to necrosis after hepatic ischemia (30). These
findings were confirmed in ob/ob mUCP2/ mice
that had higher ATP levels and increased glucose-stimulated insulin
secretion, suggesting that mUCP2 may play a role in -cell glucose
sensing and might be a link between obesity and Type 2 diabetes
(155).
mUCP3/ mice were created by two separate groups
(60, 145), and the phenotypes were shown to be consistent
in that neither line was obese. Furthermore, there were no discernable
differences between the double
mUCP1//mUCP3/ and the single
mUCP1/ mice, suggesting that mUCP3 might have no
significant thermoregulatory function (60). However, one
of the two lines of mUCP3/ mice had more coupled
mitochondria and increased ROS production (145). At the
other end of the spectrum, transgenic mice overexpressing the human
UCP3 ortholog (hUCP3
mice) were hyperphagic, were lean, had
significantly reduced adipose tissue mass, and had an increased
clearance rate for glucose (32). These data suggest that
overexpression of hUCP3 in mice could play a significant role in
resistance to obesity and the development of diabetes. It must be
pointed out that very high levels of UCP3 overexpression (about
66-fold) were achieved in this transgenic model.
Another interesting mouse model for studying the role of UCPs and fatty
acid metabolism is the transgenic A-ZIP/F-1 mouse, which has a
phenotype similar to the human severe lipoatrophic diabetes (29,
55, 112). A-ZIP/F-1 mice lack WAT (113) and could
possibly make an effective tool to study the expression of mUCPs in BAT
and in muscle.
The literature describing the physiological induction of the UCP
homologs includes many paradoxical findings, the most prominent of
which is the significant increases in mUCP2 and mUCP3 gene expression
that occur during fasting and severe food restriction. Both of the
latter conditions are situations in which efficient energy metabolism
is well recognized and not in which energy wastage would be desirable.
Significant increases in mUCP3 expression were observed in muscle of
fasted rats, but there were no changes in mitochondrial proton leak
(25). In a similar study (8), fasting caused
a fourfold increase in mUCP3 and a twofold increase in mUCP2 in muscle
of wild-type mice, whereas proton leak was unchanged (8).
Importantly, the results also showed significant differences in
respiratory quotients between mUCP3/ mice and wild-type
mice, suggesting impaired fatty acid oxidation in the absence of UCP3.
This, in conjunction with the tight correlation between the expression
of UCP3 and metabolic states in which fatty acid oxidation is high,
supports the idea that UCP3 plays a physiological role in fatty acid
metabolism (120, 121).
A mechanism to explain how UCP3 could enhance fatty acid oxidation has
been recently proposed (70) where UCP3 facilitates rapid
rates of fatty acid oxidation by acting as a mitochondrial fatty acid
efflux protein. UCP3 may act in concert with mitochondrial thioesterase(s) (MTE) to remove FFA (produced by MTE) from the matrix
and thereby liberate CoA. The relative demand for CoA during fatty acid
oxidation is high; during the complete oxidation of palmitate for
example, the relative molar requirement for CoA is 15-fold that of
palmitate. Thus the UCP3 fatty acid export cycle would liberate CoASH
to allow continuous high rates of fatty acid oxidation and other
CoASH-requiring processes. It also removes from the mitochondrion
potentially damaging molecules of fatty acid anions. Recent studies
provide some support for this hypothesis. In the mouse that
overexpresses human UCP3 (hUCP3) in muscle, MTE-1 and
lipoprotein lipase expression was increased (96). In
addition, the UCP3/ mouse and wild-type control mice
were unable to metabolize fatty acids (8). Changes in
mUCP3 expression in db/db mice and db/+ mice
treated with selective PPAR agonist were closely correlated with MTE-1
expression (33). Although the idea that UCP3 functions to
export fatty acid anions from the mitochondrial matrix remains as yet
only a hypothesis, it merits further investigation.
In summary, the data from animal studies have not as yet clearly
identified the physiological roles of mUCP2 and mUCP3. There is no
doubt, however, that UCP1 is crucial for thermogenesis, and it has been
suggested that it is the only true UCP (98). Results
generated from hUCP3 mice suggest roles for this gene in
lowering circulating levels of glucose and cholesterol and in
resistance to obesity. This possibility is supported by findings from
mUCP1 mice, thus providing some phenotypic similarities, i.e., a
potential involvement in fuel substrate partitioning and obesity.
Physiological studies that showed an induction of mUCP2 and mUCP3 by
fasting further implicate these two homologs in fatty acid oxidation.
It can be concluded from the animal studies that mUCP1 is thermogenic,
whereas mUCP3 (and possibly mUCP2) seems to play significant roles in
fatty acid oxidation, glucose clearance, and ROS production. It is far
too early to speculate on the functional properties of UCP4 and UCP5,
given the scarcity of experimental data for these two homologs.
| |
HUMAN STUDIES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
Studies of UCP mRNA expression in muscle. UCP expression has been examined quite extensively in humans. In response to peak exercise and after 1-2 h of recovery, the expression of hUCP3 was increased up to sevenfold (108), whereas two 2-h bouts of treadmill running attenuated the 24-h fasting-induced transcriptional activation of hUCP3 (69). In trained subjects, however, hUCP3 was significantly reduced (127) but was upregulated by a high-fat diet (126). Fasting increased hUCP2 and hUCP3 in both lean and obese individuals, whereas insulin failed to modify the overexpression of these genes (93). In obesity, hUCP2 was overexpressed in skeletal muscle by 1.5-fold compared with lean states and its content was increased by 15% when increased muscular contractile activity of knee extensor muscles was reduced by several weeks of low-frequency electrical stimulation (132).
Studies of UCP mRNA expression in adipose. A positive correlation has been reported between hUCP2 mRNA concentrations in adipose tissue, hUCP3 expression in the muscle, and components of metabolic rate (85). hUCP1 mRNA concentrations were higher in the intraperitoneal than in the extraperitoneal tissue in both obese and lean individuals, but morbidly obese individuals had significantly lower hUCP1 mRNA in the intraperitoneal tissue only (102). Expression of hUCP2 was increased in omental adipose tissue relative to subcutaneous adipose tissue, which may relate to the functional attributes of this subpopulation of adipocytes (42). hUCP2 mRNA in adipose tissue was inversely related to adiposity and independently linked to local plasma leptin levels but was not acutely regulated by food intake, insulin, or fatty acids (109). Increased plasma nonesterified fatty acids induced hUCP3, but not hUCP2 expression, whereas triglyceride infusion during a hyperinsulinemic clamp prevented induction of hUCP3 mRNA (76).
Expression in relation to obesity and Type 2 diabetes.
mRNA levels of hUCP3, but not hUCP2, were significantly reduced in
skeletal muscle of Type 2 diabetes patients, compared with control
subjects, and there was a positive correlation between hUCP3 expression
and the whole body insulin-mediated glucose utilization rate,
suggesting that hUCP3 regulation could be altered by insulin resistance
(83). Increased content of hUCP2 in skeletal muscle of
obese subjects was positively correlated with percent body fat, and it
coincided with reduced postabsorptive rates of lipid oxidation in
muscle (132). It has been suggested that fatty acids may
induce hUCP2 expression and tumor necrosis factor-
(TNF-) can
provoke a twofold decrease in hUCP2 mRNA levels, whereas hUCP2 in
cultured human adipocytes is increased by activators of PPAR- (146). PPAR- agonists can also induce hUCP1 in isolated
human adipocytes (43). In the Pima Indians, body mass
index (BMI) was negatively correlated with hUCP3, but not hUCP2,
expression levels, and the metabolic rate during sleep was positively
correlated with the long isoform of hUCP3, suggesting a role for hUCP3
in energy expenditure and metabolic efficiency in this population (128, 129). hUCP2 is an important negative regulator of
-cell insulin secretion; it reduces and increases the
activity of ATP-sensitive potassium channels, possibly contributing to
the loss of glucose responsiveness in obesity-related Type 2 diabetes (28). Moreover, hUCP3 stimulated glucose transport and
GLUT4 translocation to the cells in cardiac and skeletal muscle by
increasing phosphotyrosine-associated phosphoinositide 3-kinase
activity (73).
Genetic variants in the human UCPs.
Several genetic variants have been identified in the three UCPs: hUCP1,
hUCP2, and hUCP3 (149). A synopsis of the human genetic variants in the UCPs, reported to date, is provided in Table
2. Single nucleotide polymorphisms (SNPs)
have been identified in the structure and promoter regions of hUCP1
(81, 110). A SNP in the 5'-UTR, A > T, and a
structural SNP resulting in an amino acid substitution (Met229Leu) were
in linkage disequilibrium and could be associated with Type 2 diabetes
(97). Other 5'-UTR and structural missense SNPs have also
been identified in hUCP1 (Arg40Trp, Ala64Thr, Val137Met, and Lys257Asn)
but were not associated significantly with obesity- or diabetes-related
phenotypes (142). However, a SNP in the distal hUCP1
promoter, 
3826G >A (27), was significantly associated
with intraperitoneal hUCP1 mRNA (51) and could play a role
in the pathogenesis of obesity and arteriosclerosis (34, 143,
156).
|
2723T >A, 1957G >A, 866G >A, 371G > C, 13-nt deletion/insertion), and the 866G >A SNP was associated
with a high risk for obesity (52).
The gene structure of hUCP3 was also determined (1, 12),
and hUCP3 transcripts were transcribed by tissue-specific promoters involving different transcription start sites (50). hUCP3
encodes two isoforms termed hUCP3L (long transcript) and
hUCP3S (short transcript). The two transcripts differ by
the last coding exon that is missing in hUCP3S. A SNP in
the promoter of the gene, 55C > T, was associated with elevated
hUCP3 expression in male nondiabetic Pima Indians (130)
but was not associated with BMI in a French Caucasian population
(103) or a Danish Caucasian population (40);
however, it was negatively correlated with BMI in a British Caucasian
population (65). Six structural SNPs were identified in a
French Caucasian population but were not associated with obesity
(104). Another two genetic variants have been reported,
but they were not associated with obesity or Type 2 diabetes
(103). A missense mutation, Arg70Trp, was identified in an
adolescent (16 yr old) of Chinese descent with morbid obesity and Type
2 diabetes (22). However, the father of the child was nonobese but had Type 2 diabetes (21). A Chinese
population has yet to be screened to examine for the frequency of this
SNP. In the Gullah-speaking African-Americans, two SNPs and a rare mutation have been reported (5). The rare mutation that
resulted in the insertion of a premature stop codon (R143X) was
identified in a morbidly obese individual who was also heterozygous for
an exon 6 splice donor SNP (5). This compound heterozygote
represents the only known diabetic and morbidly obese individual having
one allele encoding just half of hUCP3 and one allele encoding
hUCP3S. The exon 6 splice donor polymorphism (IVS6+1G > A) was associated with elevated respiratory quotient in the Gullah
African-Americans (5) but not so in the Maywood
African-Americans (31). It should be pointed out, however,
that the genetic structure between the Maywood and the Gullah
African-Americans is markedly different. The Maywood individuals have
17% European admixture levels (106), whereas the Gullah
individuals have only 3.5% European admixture (105),
which could have a significant mediating effect on the impact of the
IVS6+1G > A SNP on the respiratory quotient of the two
populations. Functional analysis of hUCP3 mutants showed that the
IVS6+1G > A SNP, which results in a truncated protein that is
identical to hUCP3S, had equal ability to alter as
hUCP3L, when tested in heterologous yeast systems
(21, 64). Other mutations resulted in a reduced (Arg143*)
or completely absent (Arg70Trp) ability of the mutant proteins to alter
in yeast (21). Significant linkage at the hUCP2 and
hUCP3 locus has also been reported with resting metabolic rate
(P = 0.000002) and percent body fat (P = 0.04) (15). Therefore, the UCPs could perhaps be
involved in the development of obesity, but the genetic data are
inconsistent and population dependent.
In summary, the human studies provide inconclusive evidence for an
involvement of hUCP1, -2, and -3 in thermoregulation. However, the
expression levels of hUCP2 and hUCP3 during and after exercise as well
as after fasting parallel those reported for the animal studies,
suggesting a consistent role for hUCP2 and hUCP3 in substrate fuel
utilization in muscle. The genetic variants provide some evidence for a
possible involvement of the three genes in glucose disposal, resting
metabolic rate, and possibly Type 2 diabetes. However, differences in
the overall genetic structures (113) and the impact of
environmental factors (i.e., diet, exercise, climatic
temperatures) may obscure the expression of detectable and consistent
phenotypes across human populations.
| |
CONCLUSIONS AND FUTURE DIRECTIONS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
Although it was initially proposed that the recently identified
UCPs caused thermogenic uncoupling similar to that described for UCP1
in BAT, it is becoming increasingly clear that the novel UCPs have
somewhat different physiological functions. Findings from the wide
range of studies in rodents and in humans are only consistent to the
extent that fasting and some types of exercise result in the
upregulation of UCP2 and UCP3 expression. The finding that
mUCP1/ mice are cold sensitive confirms the importance
of UCP1 in thermoregulation. mUCP2/ and
mUCP3/ mice have relatively normal phenotypes, with the
common exception of increased ROS production and decreased proton
conductance. Recent findings from mUCP3/ mice, as
assessed by indirect calorimetry, revealed impairments in fatty acid
oxidation. mUCP1 and hUCP3 overexpressing mice are hyperphagic, obesity
resistant, and more efficient in glucose disposal. Therefore, a
possible role for the novel UCPs in fatty acid metabolism, glucose
clearance, and ROS production is emerging. Studies in humans are
unfortunately complicated by the fact that they are usually poorly
controlled. It is virtually impossible to impose a uniform environment
to study participants for extended periods of time, and, in the absence
of multiple twins, it is even more difficult to achieve genetic
homogeneity. The genetic variants in humans are also likely to play a
role, but variations in diet, exercise, and other genetic factors might
mask such effects. In summary, the UCP literature currently indicates
that the physiological roles of the UCP1 homologs in mammals extend
into fatty acid oxidation, energy substrate partitioning, glucose
disposal rates, insulin secretion, ROS production, apoptosis,
and aging. Much more research is needed.
| |
ACKNOWLEDGEMENTS |
|---|
This work was supported in part by U.S. Army Grant DAMD 17-97-2-7013, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Foundation for Innovation.
| |
FOOTNOTES |
|---|
Addresses for reprint requests and other correspondence: G. Argyropoulos, Pennington Biomedical Research Center, Louisiana State Univ., 6400 Perkins Road, Baton Rouge, LA 70808 (E-mail:argyrog{at}pbrc.edu) or M.-E. Harper, Dept. of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Univ. of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5 (E-mail: mharper{at}uottawa.ca).
10.1152/japplphysiol.00994.2001
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
FROM "THERMOGENIN" TO THE...
ANIMAL STUDIES
HUMAN STUDIES
CONCLUSIONS AND FUTURE...
REFERENCES
|
|---|
1.
Acin, A,
Rodriguez M,
Rique H,
Canet E,
Boutin JA,
and
Galizzi JP.
Cloning and characterization of the 5' flanking region of the human uncoupling protein 3 (UCP3) gene.
Biochem Biophys Res Commun
258:
278-283,
1999[ISI][Medline].
2.
Adams, SH.
Uncoupling protein homologs: emerging views of physiological function.
J Nutr
130:
711-714,
2000
3.
Ainscow, EK,
and
Brand MD.
Internal regulation of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes.
Eur J Biochem
266:
737-749,
1999[ISI][Medline].
4.
Argyropoulos, G,
Brown AM,
Peterson R,
Likes CE,
Watson DK,
and
Garvey WT.
Structure and organization of the human uncoupling protein 2 gene and identification of a common biallelic variant in Caucasian and African-American subjects.
Diabetes
47:
685-687,
1998[ISI][Medline].
5.
Argyropoulos, G,
Brown AM,
Willi SM,
Zhu J,
He Y,
Reitman M,
Gevao SM,
Spruill I,
and
Garvey WT.
Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.
J Clin Invest
102:
1345-1351,
1998[ISI][Medline].
6.
Arsenijevic, D,
Onuma H,
Pecqueur C,
Raimbault S,
Manning BS,
Miroux B,
Couplan E,
Alves-Guerra MC,
Goubern M,
Surwit R,
Bouillaud F,
Richard D,
Collins S,
and
Ricquier D.
Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.
Nat Genet
26:
435-439,
2000[ISI][Medline].
7.
Bauer, MF,
Hofmann S,
Neupert W,
and
Brunner M.
Protein translocation into mitochondria: the role of TIM complexes.
Trends Cell Biol
10:
25-31,
2000[ISI][Medline].
8.
Bezaire, V,
Hofmann W,
Kramer JK,
Kozak LP,
and
Harper ME.
Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(/) and wild-type mice.
Am J Physiol Endocrinol Metab
281:
E975-E982,
2001
9.
Bienengraeber, M,
Echtay KS,
and
Klingenberg M.
H+ transport by uncoupling protein (UCP-1) is dependent on a histidine pair, absent in UCP-2 and UCP-3.
Biochemistry
37:
3-8,
1998[Medline].
10.
Bing, C,
Brown M,
King P,
Collins P,
Tisdale MJ,
and
Williams G.
Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia.
Cancer Res
60:
2405-2410,
2000
11.
Block, BA.
Thermogenesis in muscle.
Annu Rev Physiol
56:
535-577,
1994[ISI][Medline].
12.
Boss, O,
Giacobino JP,
and
Muzzin P.
Genomic structure of uncoupling protein-3 (UCP3) and its assignment to chromosome 11q13.
Genomics
47:
425-426,
1998[ISI][Medline].
13.
Boss, O,
Samec S,
Desplanches D,
Mayet MH,
Seydoux J,
Muzzin P,
and
Giacobino JP.
Effect of endurance training on mRNA expression of uncoupling proteins 1, 2, and 3 in the rat.
FASEB J
12:
335-339,
1998
14.
Boss, O,
Samec S,
Kuhne F,
Bijlenga P,
Assimacopoulos-Jeannet F,
Seydoux J,
Giacobino JP,
and
Muzzin P.
Uncoupling protein-3 expression in rodent skeletal muscle is modulated by food intake but not by changes in environmental temperature.
J Biol Chem
273:
5-8,
1998
15.
Bouchard, C,
Perusse L,
Chagnon YC,
Warden C,
and
Ricquier D.
Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans.
Hum Mol Genet
6:
1887-1889,
1997
16.
Bouillaud, F,
Arechaga I,
Petit PX,
Raimbault S,
Levi-Meyrueis C,
Casteilla L,
Laurent M,
Rial E,
and
Ricquier D.
A sequence related to a DNA recognition element is essential for the inhibition by nucleotides of proton transport through the mitochondrial uncoupling protein.
EMBO J
13:
1990-1997,
1994[ISI][Medline].
17.
Bouillaud, F,
Couplan E,
Pecqueur C,
and
Ricquier D.
Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4.
Biochim Biophys Acta
1504:
107-119,
2001[Medline].
18.
Boyer, BB,
Barnes BM,
Lowell BB,
and
Grujic D.
Differential regulation of uncoupling protein gene homologues in multiple tissues of hibernating ground squirrels.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R1232-R1238,
1998
19.
Brand, MD.
Uncoupling to survive? The role of mitochondrial inefficiency in ageing.
Exp Gerontol
35:
811-820,
2000[ISI][Medline].
20.
Brand, MD,
Chien LF,
and
Diolez P.
Experimental discrimination between proton leak and redox slip during mitochondrial electron transport.
Biochem J
297:
27-29,
1994.
21.
Brown, AM,
Dolan JW,
Willi SM,
Garvey WT,
and
Argyropoulos G.
Endogenous mutations in human uncoupling protein 3 alter its functional properties.
FEBS Lett
464:
189-193,
1999[ISI][Medline].
22.
Brown, AM,
Willi SM,
Argyropoulos G,
and
Garvey WT.
A novel missense mutation, R70W, in the human uncoupling protein 3 gene in a family with type 2 diabetes.
Hum Mutat
13:
506,
1999.
23.
Brown, GC,
Lakin-Thomas PL,
and
Brand MD.
Control of respiration and oxidative phosphorylation in isolated rat liver cells.
Eur J Biochem
192:
355-362,
1990[ISI][Medline].
24.
Buemann, B,
Schierning B,
Toubro S,
Bibby B,
Sorensen T,
Dalgaard L,
Pedersen O,
and
Astrup A.
The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency.
Int J Obes Relat Metab Disord
25:
467-471,
2001[ISI][Medline].
25.
Cadenas, S,
Buckingham JA,
Samec S,
Seydoux J,
Din N,
Dulloo AG,
and
Brand MD.
UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged.
FEBS Lett
462:
257-260,
1999[ISI][Medline].
26.
Camirand, A,
Marie V,
Rabelo R,
and
Silva JE.
Thiazolidinediones stimulate uncoupling protein-2 expression in cell lines representing white and brown adipose tissues and skeletal muscle.
Endocrinology
139:
428-431,
1998
27.
Cassard-Doulcier, AM,
Bouillaud F,
Chagnon M,
Gelly C,
Dionne FT,
Oppert JM,
Bouchard C,
Chagnon Y,
and
Ricquier D.
The Bcl I polymorphism of the human uncoupling protein (ucp) gene is due to a point mutation in the 5'-flanking region.
Int J Obes Relat Metab Disord
20:
278-279,
1996[ISI][Medline].
28.
Chan, CB,
De Leo D,
Joseph JW,
McQuaid TS,
Ha XF,
Xu F,
Tsushima RG,
Pennefather PS,
Salapatek AM,
and
Wheeler MB.
Increased uncoupling protein-2 levels in -cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action.
Diabetes
50:
1302-1310,
2001
29.
Chao, L,
Marcus-Samuels B,
Mason MM,
Moitra J,
Vinson C,
Arioglu E,
Gavrilova O,
and
Reitman ML.
Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones.
J Clin Invest
106:
1221-1228,
2000[ISI][Medline].
30.
Chavin, KD,
Yang S,
Lin HZ,
Chatham J,
Chacko VP,
Hoek JB,
Walajtys-Rode E,
Rashid A,
Chen CH,
Huang CC,
Wu TC,
Lane MD,
and
Diehl AM.
Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.
J Biol Chem
274:
5692-5700,
1999
31.
Chung, WK,
Luke A,
Cooper RS,
Rotini C,
Vidal-Puig A,
Rosenbaum M,
Chua M,
Solanes G,
Zheng M,
Zhao L,
LeDuc C,
Eisberg A,
Chu F,
Murphy E,
Schreier M,
Aronne L,
Caprio S,
Kahle B,
Gordon D,
Leal SM,
Goldsmith R,
Andreu AL,
Bruno C,
DiMauro S,
Heo M,
Lowe WL, Jr,
Lowell BB,
Allison DB,
and
Leibel RL.
Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis.
Diabetes
48:
1890-1895,
1999[Abstract].
32.
Clapham, JC,
Arch JR,
Chapman H,
Haynes A,
Lister C,
Moore GB,
Piercy V,
Carter SA,
Lehner I,
Smith SA,
Beeley LJ,
Godden RJ,
Herrity N,
Skehel M,
Changani KK,
Hockings PD,
Reid DG,
Squires SM,
Hatcher J,
Trail B,
Latcham J,
Rastan S,
Harper AJ,
Cadenas S,
Buckingham JA,
Brand MD,
and
Abuin A.
Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean.
Nature
406:
415-418,
2000[Medline].
33.
Clapham, JC,
Coulthard VH,
and
Moore GB.
Concordant mRNA expression of UCP-3, but not UCP-2, with mitochondrial thioesterase-1 in brown adipose tissue and skeletal muscle in db/db diabetic mice.
Biochem Biophys Res Commun
287:
1058-1062,
2001[ISI][Medline].
34.
Clement, K,
Ruiz J,
Cassard-Doulcier AM,
Bouillaud F,
Ricquier D,
Basdevant A,
Guy-Grand B,
and
Froguel P.
Additive effect of AG (3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the 3-adrenergic receptor gene on weight gain in morbid obesity.
Int J Obes Relat Metab Disord
20:
1062-1066,
1996[ISI][Medline].
35.
Commins, SP,
Watson PM,
Frampton IC,
and
Gettys TW.
Leptin selectively reduces white adipose tissue in mice via a UCP1-dependent mechanism in brown adipose tissue.
Am J Physiol Endocrinol Metab
280:
E372-E377,
2001
36.
Commins, SP,
Watson PM,
Levin N,
Beiler RJ,
and
Gettys TW.
Central leptin regulates the UCP1 and ob genes in brown and white adipose tissue via different -adrenoceptor subtypes.
J Biol Chem
275:
33059-33067,
2000
37.
Commins, SP,
Watson PM,
Padgett MA,
Dudley A,
Argyropoulos G,
and
Gettys TW.
Induction of uncoupling protein expression in brown and white adipose tissue by leptin.
Endocrinology
140:
292-300,
1999
38.
Considine, MJ,
Daley DO,
and
Whelan J.
The expression of alternative oxidase and uncoupling protein during fruit ripening in mango.
Plant Physiol
126:
1619-1629,
2001
39.
Cortright, RN,
Zheng D,
Jones JP,
Fluckey JD,
DiCarlo SE,
Grujic D,
Lowell BB,
and
Dohm GL.
Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation.
Am J Physiol Endocrinol Metab
276:
E217-E221,
1999
40.
Dalgaard, LT,
Sorensen TI,
Drivsholm T,
Borch-Johnsen K,
Andersen T,
Hansen T,
and
Pedersen O.
A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population.
J Clin Endocrinol Metab
86:
1398-1402,
2001
41.
Diehl, AM,
and
Hoek JB.
Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control "the benefits of losing control."
J Bioenerg Biomembr
31:
493-506,
1999[ISI][Medline].
42.
Digby, JE,
Crowley VE,
Sewter CP,
Whitehead JP,
Prins JB,
and
O'Rahilly S.
Depot-related and thiazolidinedione-responsive expression of uncoupling protein 2 (UCP2) in human adipocytes.
Int J Obes Relat Metab Disord
24:
585-592,
2000[ISI][Medline].
43.
Digby, JE,
Montague CT,
Sewter CP,
Sanders L,
Wilkison WO,
O'Rahilly S,
and
Prins JB.
Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes.
Diabetes
47:
138-141,
1998[Abstract].
44.
Dulloo, AG,
and
Samec S.
Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered.
Br J Nutr
86:
123-139,
2001[ISI][Medline].
45.
Echtay, KS,
Winkler E,
Bienengraeber M,
and
Klingenberg M.
Site-directed mutagenesis identifies residues in uncoupling protein (UCP1) involved in three different functions.
Biochemistry
39:
3311-3317,
2000[Medline].
46.
Echtay, KS,
Winkler E,
Frischmuth K,
and
Klingenberg M.
Uncoupling proteins 2 and 3 are highly active H+ transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone).
Proc Natl Acad Sci USA
98:
1416-1421,
2001
47.
Echtay, KS,
Winkler E,
and
Klingenberg M.
Coenzyme Q is an obligatory cofactor for uncoupling protein function.
Nature
408:
609-613,
2000[Medline].
48.
Emilsson, V,
Summers RJ,
Hamilton S,
Liu YL,
and
Cawthorne MA.
The effects of the 3-adrenoceptor agonist BRL 35135 on UCP isoform mRNA expression.
Biochem Biophys Res Commun
252:
450-454,
1998[ISI][Medline].
49.
Enerback, S,
Jacobsson A,
Simpson EM,
Guerra C,
Yamashita H,
Harper ME,
and
Kozak LP.
Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.
Nature
387:
90-94,
1997[Medline].
50.
Esterbauer, H,
Oberkofler H,
Krempler F,
Strosberg AD,
and
Patsch W.
The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents.
J Biol Chem
275:
36394-36399,
2000
51.
Esterbauer, H,
Oberkofler H,
Liu YM,
Breban D,
Hell E,
Krempler F,
and
Patsch W.
Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus.
J Lipid Res
39:
834-844,
1998
52.
Esterbauer, H,
Schneitler C,
Oberkofler H,
Ebenbichler C,
Paulweber B,
Sandhofer F,
Ladurner G,
Hell E,
Strosberg AD,
Patsch JR,
Krempler F,
and
Patsch W.
A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.
Nat Genet
28:
178-183,
2001[ISI][Medline].
53.
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].
54.
Friedman, JM.
Obesity in the new millennium.
Nature
404:
632-634,
2000[Medline].
55.
Gavrilova, O,
Marcus-Samuels B,
Leon LR,
Vinson C,
and
Reitman ML.
Leptin and diabetes in lipoatrophic mice.
Nature
403:
850-851,
2000[Medline].
56.
Giacobino, JP.
Effects of dietary deprivation, obesity and exercise on UCP3 mRNA levels.
Int J Obes Relat Metab Disord
23, Suppl 6:
S60-S63,
1999.
57.
Golozoubova, V,
Hohtola E,
Matthias A,
Jacobsson A,
Cannon B,
and
Nedergaard J.
Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold.
FASEB J
15:
2048-2050,
2001
58.
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
59.
Gong, DW,
He Y,
and
Reitman ML.
Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes.
Biochem Biophys Res Commun
256:
27-32,
1999[ISI][Medline].
60.
Gong, DW,
Monemdjou S,
Gavrilova O,
Leon LR,
Marcus-Samuels B,
Chou CJ,
Everett C,
Kozak LP,
Li C,
Deng C,
Harper ME,
and
Reitman ML.
Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.
J Biol Chem
275:
16251-16257,
2000
61.
Gonzalez-Barroso, MM,
Fleury C,
Jimenez MA,
Sanz JM,
Romero A,
Bouillaud F,
and
Rial E.
Structural and functional study of a conserved region in the uncoupling protein UCP1: the three matrix loops are involved in the control of transport.
J Mol Biol
292:
137-149,
1999[ISI][Medline].
62.
Gonzalez-Barroso, MM,
Fleury C,
Levi-Meyrueis C,
Zaragoza P,
Bouillaud F,
and
Rial E.
Deletion of amino acids 261-269 in the brown fat uncoupling protein converts the carrier into a pore.
Biochemistry
36:
10930-10935,
1997[Medline].
63.
Grujic, D,
Susulic VS,
Harper ME,
Himms-Hagen J,
Cunningham BA,
Corkey BE,
and
Lowell BB.
3-Adrenergic receptors on white and brown adipocytes mediate 3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice.
J Biol Chem
272:
17686-17693,
1997
64.
Hagen, T,
Zhang CY,
Slieker LJ,
Chung WK,
Leibel RL,
and
Lowell BB.
Assessment of uncoupling activity of the human uncoupling protein 3 short form and three mutants of the uncoupling protein gene using a yeast heterologous expression system.
FEBS Lett
454:
201-206,
1999[ISI][Medline].
65.
Halsall, D,
Luan J,
Saker P,
Huxtable S,
Farooqi I,
Keogh J,
Wareham N,
and
O'Rahilly S.
Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population.
Int J Obes Relat Metab Disord
25:
472-477,
2001[ISI][Medline].
66.
Hanak, P,
and
Jezek P.
Mitochondrial uncoupling proteins and phylogenesis
UCP4 as the ancestral uncoupling protein.
FEBS Lett
495:
137-141,
2001[ISI][Medline].
67.
Harper, ME,
and
Brand MD.
The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status.
J Biol Chem
268:
14850-14860,
1993
68.
Hidaka, S,
Kakuma T,
Yoshimatsu H,
Sakino H,
Fukuchi S,
and
Sakata T.
Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart.
Diabetes
48:
430-435,
1999[Abstract].
69.
Hildebrandt, AL,
and
Neufer PD.
Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle.
Am J Physiol Endocrinol Metab
278:
E1078-E1086,
2000
70.
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
71.
Himms-Hagen, J.
Brown adipose tissue thermogenesis and obesity.
Prog Lipid Res
28:
67-115,
1989[ISI][Medline].
72.
Himms-Hagen, J.
Brown adipose tissue thermogenesis: interdisciplinary studies.
FASEB J
4:
2890-2898,
1990[Abstract].
73.
Huppertz, C,
Fischer BM,
Kim YB,
Kotani K,
Vidal-Puig A,
Slieker LJ,
Sloop KW,
Lowell BB,
and
Kahn BB.
Uncoupling protein 3 (UCP3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism.
J Biol Chem
276:
12520-12529,
2001
74.
Jezek, P.
Fatty acid interaction with mitochondrial uncoupling proteins.
J Bioenerg Biomembr
31:
457-466,
1999[ISI][Medline].
75.
Kagawa, Y,
Cha SH,
Hasegawa K,
Hamamoto T,
and
Endo H.
Regulation of energy metabolism in human cells in aging and diabetes: FoF(1), mtDNA, UCP, and ROS.
Biochem Biophys Res Commun
266:
662-676,
1999[ISI][Medline].
76.
Khalfallah, Y,
Fages S,
Laville M,
Langin D,
and
Vidal H.
Regulation of uncoupling protein-2 and uncoupling protein-3 mRNA expression during lipid infusion in human skeletal muscle and subcutaneous adipose tissue.
Diabetes
49:
25-31,
2000[Abstract].
77.
Klannemark, M,
Orho M,
and
Groop L.
No relationship between identified variants in the uncoupling protein 2 gene and energy expenditure.
Eur J Endocrinol
139:
217-223,
1998[Abstract].
78.
Klingenberg, M,
Echtay KS,
Bienengraeber M,
Winkler E,
and
Huang SG.
Structure-function relationship in UCP1.
Int J Obes Relat Metab Disord
23, Suppl 6:
S24-S29,
1999.
79.
Koehler, CM.
Protein translocation pathways of the mitochondrion.
FEBS Lett
476:
27-31,
2000[ISI][Medline].
80.
Kozak, LP,
and
Harper ME.
Mitochondrial uncoupling proteins in energy expenditure.
Annu Rev Nutr
20:
339-363,
2000[ISI][Medline].
81.
Kozak, UC,
Kopecky J,
Teisinger J,
Enerback S,
Boyer B,
and
Kozak LP.
An upstream enhancer regulating brown-fat-specific expression of the mitochondrial uncoupling protein gene.
Mol Cell Biol
14:
59-67,
1994
82.
Kozak, LP,
and
Koza RA.
Mitochondria uncoupling proteins and obesity: molecular and genetic aspects of UCP1.
Int J Obes Relat Metab Disord
23, Suppl 6:
S33-S37,
1999.
83.
Krook, A,
Digby J,
O'Rahilly S,
Zierath JR,
and
Wallberg-Henriksson H.
Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients.
Diabetes
47:
1528-1531,
1998
84.
Laloi, M,
Klein M,
Riesmeier JW,
Muller-Rober B,
Fleury C,
Bouillaud F,
and
Ricquier D.
A plant cold-induced uncoupling protein.
Nature
389:
135-136,
1997[Medline].
85.
Langin, D,
Larrouy D,
Barbe P,
Millet L,
Viguerie-Bascands N,
Andreelli F,
Laville M,
and
Vidal H.
Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and
