UCP2 and UCP3 in muscle controlling body metabolism
Nutrition and Toxicology Research Institute Maastricht
(NUTRIM)
1 Department of Human Biology, Maastricht University, The
Netherlands
2 Department of Movement Sciences, Maastricht University, The
Netherlands
* Present address: Department of Human Biology, Maastricht University, PO Box
616, 6200 MD Maastricht, The Netherlands
(e-mail: p.schrauwen{at}hb.unimaas.nl )
Accepted 13 May 2002
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Summary |
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Key words: uncoupling protein, energy expenditure, obesity, diabetes, fatty acid metabolism
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Introduction |
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According to the Nobel-prize-winning chemiosmotic hypothesis of Mitchell
(Mitchell, 1966), the protons
are transported to the cytosolic side of the inner mitochondrial membrane by a
series of reactions. This eventually generates a proton gradient across the
membrane, which causes protons to flow back across the inner mitochondrial
membrane through a so-called F0F1-complex. The energy
thus generated is used by ATPase to transform ADP into ATP. In this way,
substrate oxidation is coupled to the formation of ATP. In living cells, and
in animals/humans under resting conditions, ATP is continuously consumed by,
among other processes, the Na+/K+ pump
(Na+/K+-ATPase), which is responsible for approximately
20 % of ATP consumption, protein turnover (12-25 %) and the Ca2+
pump (Ca2+-ATPase) (4-6 %). Furthermore, in active animals/humans,
muscle contraction is a significant contributor to ATP consumption.
The coupling between substrate oxidation and ATP formation is not 100 %
efficient. The proton gradient, which is built up by the oxidation of
substrates, can be reduced by so-called proton leaks, thereby diminishing the
efficiency of ATP synthesis from substrate oxidation and thus dissipating
energy as heat. The mechanism by which proton leaks reduce the proton gradient
is not completely understood, but it has been proposed that uncoupling
proteins (UCPs) are involved. These proteins could either transport protons
into the mitochondrial matrix (Klingenberg
et al., 1999) or transport non-esterified fatty acid anions out of
the matrix in a process called fatty acid cycling
(Jezek et al., 1998
). Both
these processes would reduce the proton gradient across the inner
mitochondrial membrane (Fig.
1).
|
Although the rationale for proton leaks is not understood, they are a feature common to all living cells.
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Adaptive thermogenesis |
---|
This feature of brown adipose tissue has led to the search for and
identification of a protein responsible for this proton leak. In 1978, it was
demonstrated that a 32kDa mitochondrial membrane protein, then called
uncoupling protein or thermogenin and later renamed UCP1, was responsible for
the thermogenic activity of brown adipose tissue
(Nicholls et al., 1978).
Exposure of mammals to cold results in an acute increase in metabolic rate
through shivering thermogenesis, i.e. muscular activity producing heat.
However, if cold exposure is prolonged, shivering ceases, but metabolic rate
remains elevated. This non-shivering thermogenesis is mainly accounted for by
an increase in the activity of the brown adipose tissue and is accompanied by
a marked increase in the expression of UCP1
(Desautels et al., 1978
).
Upon overfeeding, the expression of UCP1 in the brown adipose tissue of
rodents is also upregulated, and this correlates closely with decreased
metabolic efficiency and the prevention of the development of obesity
(Himms-Hagen, 1984). In
contrast, fasting is associated with an increase in metabolic efficiency and a
decrease in UCP1 expression and activity
(Rothwell et al., 1984
). These
findings illustrate the importance of UCP1 in the regulation of body
temperature and energy balance in rodents.
More definitive evidence for a unique role of UCP1 in adaptive
thermogenesis came with the creation of mice lacking UCP1. These mice are
indeed unable to maintain their body temperature when exposed to cold
(Enerback et al., 1997).
Gradual acclimatisation to a colder environment extends the life span of these
mice, but only by maintaining shivering thermogenesis. When shivering
thermogenesis can no longer be maintained, these mice are no longer able to
survive in the cold. This finding clearly illustrates that no other protein or
hormone could substitute for the absence of UCP1 in adaptive non-shivering
thermogenesis (Golozoubova et al.,
2001
). Similarly, it has been shown that brown fat cells lacking
UCP1 do not show the usual increase in the rate of oxygen consumption after
administration of noradrenaline
(Nedergaard et al., 2001
).
Together, these findings indicate that UCP1 plays a major role in adaptive
non-shivering thermogenesis, at least in rodents.
In humans, the site of adaptive thermogenesis might not be restricted to
brown adipose tissue. Adult humans have no large deposits of brown adipose
tissue, although brown adipose fat cells may be present in small numbers
within the white adipose tissue (Lean et
al., 1986). As a result of the low content of brown adipose tissue
from adult humans, its contribution to adrenaline-induced thermogenesis was
estimated to be maximally 25%, so other tissues must therefore be involved
(Astrup et al., 1985
). The same
study showed that, in humans, skeletal muscle is the most important tissue for
adaptive thermogenesis, accounting for up to 50% of adrenaline-induced
thermogenesis. Comparable results were found by Simonsen et al.
(1993
), who estimated that 40%
of the increase in thermogenesis after adrenaline administration could be
attributed to skeletal muscle. Since UCP1, which is responsible for the
thermogenic activity of brown adipose tissue, is not present in skeletal
muscle, searches have been made for other (uncoupling) proteins that could
contribute to adaptive thermogenesis in skeletal muscle.
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UCP2 as a regulator of energy metabolism |
---|
Using these polymorphisms, positive associations between the UCP2 gene and
energy expenditure have been found (Astrup
et al., 1999; Buemann et al.,
2001
; Walder et al.,
1998
), although one study found no such association
(Klannemark et al., 1998
).
Studies focusing on the association between UCP2 polymorphisms and obesity
(defined by body mass index or body composition) showed more diverse results,
with some studies reporting a positive association
(Cassell et al., 1999
;
Esterbauer et al., 2001
;
Evans et al., 2001
;
Yanovski et al., 2000
) and
others no association (Comuzzie et al.,
2000
; Dalgaard et al.,
1999
; Elbein et al.,
1997
; Kubota et al.,
1998
; Lentes et al.,
1999
; Otabe et al.,
1998
; Shiinoki et al.,
1999
; Urhammer et al.,
1997
) between UCP2 and obesity
(Table 1).
|
Overall, these studies do reveal an association between UCP2 and energy
metabolism, but this association is apparently not always reflected in
obesity. It could be argued that the latter is surprising, considering that
the development of obesity results from a misbalance between energy
expenditure and energy intake. It is therefore unlikely that the phenotype
obesity can be fully explained by (polymorphism in) a single gene. For
example, an effect of UCP2 on metabolic rate could be compensated for by
increased spontaneous physical activity and/or reduced food intake, even
though a reduced metabolic rate predisposes to obesity
(Ravussin et al., 1988;
Trayhurn and Jennings, 1988
;
Tremblay et al., 1989
).
Therefore, the lack of association between UCP2 and obesity, as observed in
the majority of studies, should not be interpreted as evidence against an
important role for UCP2 in the regulation of (human) energy metabolism.
A more direct way to examine the relationship between UCP2 and (human)
energy metabolism is to study UCP2 mRNA and protein expression experimentally
together with simultaneous measurements of energy expenditure. Using this
approach, it was shown that UCP2 mRNA levels in adipose tissue were positively
related to resting metabolic rate (which accounts for 60-70% of total 24 h
energy expenditure) (Barbe et al.,
1998). Furthermore, administration of thyroid hormone to humans,
resulting in a pronounced increase in energy expenditure, was shown to
upregulate UCP2 mRNA expression in skeletal muscle
(Barbe et al., 2001
). These
findings suggest that UCP2 is related to energy expenditure and could,
therefore, be involved in the development of obesity. Indeed, it was shown in
rodents that UCP2 mRNA expression is higher in obesity-resistant (A/J) mice
than in obesity-prone (B6) mice. Furthermore, UCP2 mRNA expression was
upregulated after feeding a high-fat diet in the A/J strain but not in the B6
strain mice, suggesting that the lack of upregulation of UCP2 in the latter
could contribute to the high susceptibility to obesity of these mice
(Fleury et al., 1997
).
In humans, reduced UCP2 mRNA expression has been reported in the white
adipose tissue (Oberkofler et al.,
1998) and skeletal muscle
(Nordfors et al., 1998
) of
obese subjects. Recently, a common polymorphism in the promotor of the human
UCP2 gene has been described that influences UCP2 transcription when expressed
in a cell system and is associated with increased UCP2 mRNA expression in
human adipose tissue. Interestingly, this polymorphism was associated with a
slightly reduced risk of obesity and, since the polymorphism is very common,
it was concluded that it might account for up to 15% of obesity in humans
(Esterbauer et al., 2001
).
Although this value might be too optimistic, the study does indicate that
functional mutations in the UCP2 gene that affect UCP2 expression can
influence the regulation of body mass in humans. Taken together, these studies
indicate that UCP2 is, in one way or another, related to energy metabolism and
obesity in rodents and humans.
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Alternative functions of UCP2: prevention of the formation of reactive oxygen species and as a regulator of [ATP]:[ADP] ratio |
---|
A role for UCP2 as a regulator of ROS production had already been suggested
by Nègre-Salvayre et al.
(1997), who showed that the
addition of GDP to brown adipocytes resulted in an increase in the electrical
potential across the inner mitochondrial membrane and in ROS production. They
assumed that this effect of GDP was due to inhibition of uncoupling activity
by GDP. The same effect of GDP on ROS production was observed in liver
mitochondria from nonparenchymal cells, but not in mitochondria from
hepatocytes. Since the latter lack UCP2, they suggested that UCP2 might act to
modulate ROS production and that UCP2 could, like UCP1, also be inhibited by
the addition of GDP.
Apart from a role in regulating ROS production, UCP2 has also been
implicated in the development of diabetes mellitus. Adenovirus-mediated
overexpression of UCP2 in pancreatic islets has been shown to result in a
decrease in glucose-stimulated insulin secretion
(Chan et al., 2001). Driven by
this finding, Zhang et al.
(2001
) created mice lacking
UCP2 and studied glucose metabolism and insulin secretion in these mice. In
accordance with the results of Arsenijevic et al.
(2000
), they found no effect of
the absence of UCP2 on body mass or cold-induced thermogenesis. However,
UCP2-knockout mice had significantly lower glucose levels and elevated insulin
concentrations, and the ß-cells of UCP2-knockout mice showed increased
insulin secretion. The mechanism behind these effects may originate from the
influence of UCP2 on the [ATP]/[ADP] ratio. In ß-cells, an increase in
[ATP] and/or [ATP]/[ADP] ratio (resulting from the metabolism of glucose)
closes a membrane-bound ATP-sensitive K+ channel, resulting in the
influx of Ca2+ and subsequent insulin secretion.
Although these findings are interesting, they are difficult to interpret.
At first sight, the findings suggest that a reduction in UCP2 expression in
ß-cells would be beneficial for the treatment of diabetes. However, the
contrary seems to be the case for other tissues expressing UCP2. As discussed
above, high levels of UCP2 expression in white adipose tissue and/or skeletal
muscle are associated with a reduced risk of developing obesity, which is the
most important risk factor for the development of type 2 diabetes mellitus.
Furthermore, overexpression of UCP1 in skeletal muscle was recently shown to
result in resistance to diet-induced diabetes
(Li et al., 2000). These data
suggest that high levels of UCP expression would be beneficial in the
prevention/treatment of diabetes mellitus. In addition, assuming a role for
UCP2 in the regulation of ROS production, a low level of UCP2 expression would
increase ROS production, which is particularly dangerous in the case of
diabetes because recent data indicate that ROS production is the link between
elevated glucose levels and hyperglycaemic damage
(Nishikawa et al., 2000
). In
fact, overexpression of UCP1 in endothelial cells reduced ROS production and
prevented hyperglycaemic damage (Nishikawa
et al., 2000
). Together, these results indicate that simply
downregulating UCP2 might not have the desired outcome regarding the
prevention/treatment of diabetes mellitus.
Taken together, although studies using UCP2-knockout mice have given insight into the putative functions of this novel uncoupling protein, we are still a long way from completely understanding the function of UCP2. What seems to be clear, however, is that UCP2 indeed uncouples oxidative phosphorylation and thereby controls the [ATP]/[ADP] ratio and inner mitochondrial membrane proton gradient. It is well known that the [ATP]/[ADP] ratio plays an important role in the overall regulation of cellular function, making interpretation of studies with UCP2-knockout mice difficult. The fact that abolishing UCP2 expression results in interesting phenotypes indeed illustrates the importance of maintaining the [ATP]/[ADP] ratio and inner mitochondrial membrane proton gradient within narrow ranges. However, it does not explain the physiological function of UCP2, because genetic manipulation of UCP2 cannot distinguish between the effect of manipulating [ATP]/[ADP] ratio and the effect of physiological induction of UCP2. Therefore, studies manipulating UCP2 expression within the physiological range, as well as studies examining the regulation of UCP2 in different tissues, are needed to obtain insight into the physiological function of UCP2.
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Is UCP3 the skeletal muscle analogue of the brown adipose tissue UCP1? |
---|
|
To examine directly whether UCP3 mRNA is related to energy metabolism in
humans, we used respiration chambers to measure human energy metabolism in
detail and reverse transcriptase polymerase chain reaction (RT-PCR) to measure
skeletal muscle UCP3 mRNA expression. We observed a positive correlation
between sleeping metabolic rate and 24 h energy expenditure and the expression
of UCP3 mRNA in Pima Indians (Schrauwen et
al., 1999b). The lack of similar relationships in other studies
(Bao et al., 1998
) might be due
to genetic difference between the populations studied. In this regard, it is
important to note that sleeping metabolic rate in Pima Indians is a strong
predictor of weight gain (Ravussin et al.,
1988
).
Further evidence for a relationship between UCP3 expression and energy
metabolism comes from the finding that UCP3 mRNA expression is upregulated
after thyroid hormone treatment, which is known to increase thermogenesis both
in rodents (Gong et al., 1997)
and in humans (Barbe et al.,
2001
). Furthermore, like UCP1 in brown adipose tissue, UCP3 is
upregulated after the consumption of a high-fat diet in rodents
(Gong et al., 1999
) and humans
(Schrauwen et al., 2001b
).
Finally, we and others have observed that UCP3 mRNA expression and UCP3
protein content are reduced after endurance training
(Boss et al., 1998a
;
Schrauwen et al., 1999a
) and
after weight reduction (Schrauwen et al.,
2000
; Vidal-Puig et al.,
1999
), conditions both characterized by a reduced resting
metabolic rate and/or increased metabolic efficiency.
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UCP3 as a regulator of fuel metabolism |
---|
Experiments with UCP3-knockout mice further weakened the likelihood of an
important role for UCP3 in the regulation of energy metabolism: these mice
have no apparent phenotype, i.e. they are not obese and do not have an altered
metabolic rate (Gong et al.,
2000; Vidal-Puig et al.,
2000
). However, mice overexpressing UCP3 eat considerably more
than their wild-type littermates, but do not become obese, suggesting that
metabolic rate is increased in these animals
(Clapham et al., 2000
). Taken
together, these results indicate that UCP3 is indeed able to uncouple
oxidative phosphorylation in vivo, thereby dissipating energy as
heat. However, as for UCP2, the effect of UCP3 on energy expenditure may be
secondary to its primary physiological function. Again, the question arises as
to what the function of this novel uncoupling protein could be.
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Does UCP3 play a role in type 2 diabetes mellitus? |
---|
In contrast, skeletal muscle is an important organ in maintaining glucose
homeostasis, and diabetes mellitus is characterized by disturbances in
skeletal muscle glucose metabolism. As mentioned above, overexpression of UCP1
in skeletal muscle results in resistance to diet-induced diabetes and improved
skeletal muscle glucose transport (Li et
al., 2000). In addition, mice overexpressing UCP3 have reduced
plasma glucose and insulin levels (Clapham
et al., 2000
). Recently, Huppertz et al.
(2001
) showed that
overexpression of UCP3 in L6 myotubes increases glucose uptake through an
increased recruitment of the glucose transporter GLUT4 to the cell surface. In
this context, it is interesting to note that exposure of rats to cold (4
°C), which is known to increase glucose utilization, leads to a concerted
upregulation of UCP3 and GLUT4 mRNA expression after 6-24h and a concerted
downregulation of the expression of both genes after 6 days
(Lin et al., 1998
). Also,
after endurance exercise, UCP3 and GLUT4 mRNA expression increased in parallel
(Tsuboyama-Kasaoka et al.,
1998
). These findings suggest that there is a close relationship
between UCP3 expression and glucose metabolism in skeletal muscle. A
characteristic of skeletal muscle is that it consists of different types of
muscle fibres, with different capacities to oxidize glucose and fatty acids.
Type 1 muscle fibres are equipped to oxidize fatty acids, whereas type 2b
muscle fibre are mainly able to oxidize glucose. In accordance with a
relationship between UCP3 and glucose metabolism, we recently showed, using
immunofluorescence, that UCP3 is expressed more abundantly in glycolytic type
2b muscle fibres than in oxidative type 1 muscle fibres
(Hesselink et al., 2001
).
One proposed mechanism by which UCP3 could affect glucose uptake is
via AMP kinase. The uncoupling of mitochondria results in a
diminished ATP production and, hence, an increase in AMP concentration. The
latter is known to activate AMP kinase, an enzyme responsible for the
phosphorylation of key enzymes that control metabolic flux, including glucose
uptake (via GLUT4 translocation)
(Winder and Hardie, 1999).
Taken together, these findings indicate a relationship between the presence of
UCP3 and glucose metabolism and suggest that an impaired regulation of UCP3
could be involved in the aetiology of diabetes mellitus. However, direct
comparisons of UCP3 mRNA levels in type 2 diabetic subjects with those in
healthy controls revealed both decreased
(Krook et al., 1998
) and
increased (Bao et al., 1998
;
Vidal et al., 1999
) UCP3 mRNA
expression. Although the reason for this discrepancy is not clear, it is
possible that differences in diet, fasting period or exercise prior to the
sampling of the biopsy could have contributed to the observed differences.
Therefore, we recently determined UCP3 protein content, which is thought to be
less variable than UCP3 mRNA expression, in type 2 diabetic subjects and
healthy controls and found that UCP3 protein content in type 2 diabetic
subjects was only 50 % of that in healthy subjects
(Schrauwen et al., 2001a
).
Whether this means that UCP3 is indeed involved in the aetiology of diabetes
mellitus cannot be determined from these results. However, the C
T
substitution in the UCP3 promotor mentioned above, associated with increased
UCP3 mRNA expression, was recently found to be associated with a decreased
risk of developing type 2 diabetes mellitus
(Meirhaeghe et al., 2000
).
If UCP3 is indeed involved in the aetiology of type 2 diabetes mellitus, it
is a potential pharmacological target for the treatment of diabetes. For
example, thiazolidinediones, a novel class of blood-glucose-lowering drugs
that improve glycaemic control and insulin-sensitivity
(Day, 1999), were shown to
upregulate skeletal muscle UCP3 mRNA expression in rodents
(Emilsson et al., 2000
;
Oberkofler et al., 2000
). It
is not known whether the upregulation of UCP3 expression by thiazolidinediones
is responsible for the improved glucose tolerance or whether similar effects
can be observed in humans. However, if this is the case, agents specifically
able to upregulate UCP3 expression could be helpful in the treatment of
diabetes mellitus.
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Is UCP3 a transporter of fatty acids? |
---|
A role for UCP3 in fatty acid metabolism would also be consistent with the
observed upregulation of UCP3 after thyroid hormone treatment
(Barbe et al., 2001;
Gong et al., 1997
), high-fat
feeding (Gong et al., 1999
;
Schrauwen et al., 2001b
) and
cold exposure (Lin et al.,
1998
) since, in these situations, both thermogenesis and fat
oxidation are stimulated. The fasting-induced upregulation of UCP3 and
subsequent downregulation of UCP3 (below baseline levels) during refeeding
provide further evidence that UCP3 is, in fact, more involved in fatty acid
metabolism than in energy metabolism
(Samec et al., 1999a
). Also,
the upregulation of UCP3 mRNA expression after acute exercise
(Pilegaard et al., 2000
) could
be attributed to increased metabolic rate and increased fat oxidation in the
post-exercise period. To separate these effects, we examined the combined
effect of acute exercise and glucose administration, thereby preventing the
usual rise in plasma FFA levels and rate of fat oxidation, on UCP3 mRNA
expression. We found that UCP3 mRNA is upregulated after exercise only in the
fasted state and that this increase could be completely abolished by
administration of glucose (Schrauwen et
al., 2002a
), indicating that UCP3 is indeed more closely involved
in fatty acid metabolism than in energy metabolism.
However, conditions in which UCP3 is downregulated are not characterized by
low plasma FFA levels and/or low rates of fatty acid oxidation. For example,
UCP3 has repeatedly been shown to be downregulated after endurance training
(Boss et al., 1998a; Schrauwen
et al., 1999a
,
2001c
), a condition in which
fat oxidative capacity is enhanced
(Holloszy and Coyle, 1984
). In
addition, weight reduction leads to an increase in capacity to oxidise fat and
a decrease in UCP3 mRNA expression and in UCP3 protein content
(Schrauwen et al., 2000
;
Vidal-Puig et al., 1999
).
Finally, type 1 muscle fibres, characterized by a high capacity to oxidise
fat, have the lowest expression of UCP3. These findings indicate that UCP3 is
downregulated in conditions of enhanced capacity to oxidise fat and
unregulated in conditions in which fatty acid delivery exceeds the capacity to
oxidise fat, eventually leading to an increase in plasma FFA levels (fasting,
acute exercise).
As mentioned in the Introduction, UCPs could act as fatty acid anion
transporters, transporting fatty acid anions out of the mitochondrial matrix
(Jezek et al., 1998). We
recently postulated that UCP3 might act as a fatty acid anion transporter in
situations in which delivery of fatty acids to the mitochondria exceeds their
capacity to oxidise fat (Schrauwen et al.,
2001c
). In these conditions, neutral fatty acids might accumulate
in the cytoplasm, `flip-flop' into the mitochondrial matrix and equilibrate
with the pH gradient, thereby delivering both neutral and fatty acid anions to
the matrix. Since fatty acid anions cannot flip-flop back, and since neither
fatty acid anions nor neutral fatty acids can be metabolized inside the
mitochondrial matrix (because no fatty acyl-CoA synthetase is present), the
export of fatty acid anions out of the matrix by UCP3 might prevent the
accumulation of fatty acids inside the matrix
(Fig. 2). At the same time, an
alternative hypothesis was postulated by Himms-Hagen and Harper
(2001
). In short, they also
believe that UCP3 exports fatty acid anions from the mitochondrial matrix;
however, according to their hypothesis, fatty acid anions are delivered by
hydrolysis of acyl-CoA by mitochondrial thioesterases, thereby producing a
fatty acid anion inside the matrix. Support for their hypothesis is provided
by the observation that mice overexpressing UCP3 also show increased
expression of mitochondrial thioesterases
(Moore et al., 2001
). However,
the physiological importance of mitochondrial thioesterases is not fully
established, and both hypotheses should be examined further.
|
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Concluding remarks |
---|
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Acknowledgments |
---|
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