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At least 19 recordsLinked to original sources
PubMed2000

Mitochondrial import of the long and short isoforms of human uncoupling protein 3.

Human uncoupling protein 3 (UCP3) has two RNA transcripts that arise from the differential processing of the same gene product. One encodes the full length protein (UCP3L) while the other encodes a truncated version (UCP3S) lacking the sixth membrane spanning domain. The roles of the two isoforms are not known, but a mutation that decreases the proportion of UCP3L decreases fat oxidation and increases susceptibility to obesity. In the ADP/ATP carrier, a protein closely related to UCP3, the sixth membrane spanning domain is required for insertion into the inner membrane. Therefore, defective membrane insertion of UCP3S may account for the different effects of the two isoforms in vivo. We investigated mitochondrial import of the two UCP3 isoforms. When epitope-tagged versions of UCP3S and UCP3L were expressed in COS7 cells, both were inserted into the mitochondrial inner membrane. Translation in vitro followed by incubation with isolated mitochondria showed that both isoforms were inserted into the inner membrane, however, the insertion of UCP3S was significantly slower.

Animals↗
PubMed1999

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.

The human uncoupling protein 3 gene generates two mRNA transcripts, uncoupling protein 3L and uncoupling protein 3S, which are predicted to encode long and short forms of the uncoupling protein 3 protein, respectively. While uncoupling protein 3L is similar in length to the other known uncoupling proteins, uncoupling protein 3S lacks the last 37 C-terminal residues. A splice site mutation in the human uncoupling protein 3 gene, resulting in the exclusive expression of uncoupling protein 3S, and a number of point mutations in the uncoupling protein 3 gene have been described. This study compares the biochemical activity of uncoupling protein 3S as well as three mutants of the uncoupling protein 3 gene (V9M, V102I, R282C) with that of uncoupling protein 3L utilizing a yeast expression system. All proteins were expressed at similar levels and had qualitatively similar effects on parameters related to the uncoupling function. Both uncoupling protein 3S and uncoupling protein 3L decreased the yeast growth rate by 35 and 52%, increased the whole yeast basal O2 consumption by 26 and 48%, respectively, and decreased the mitochondrial membrane potential as measured in whole yeast by uptake of the fluorescent potential-sensitive dye 3'3-dihexyloxacarbocyanine iodide. In isolated mitochondria, uncoupling protein 3S and uncoupling protein 3L caused a similar (33 and 35%, respectively) increase in state 4 respiration, which was relatively small compared to uncoupling protein 1 (102% increase). A truncated version of uncoupling protein 3S, lacking the last three C-terminal residues, Tyr, Lys and Gly, that are part of a carrier motif that is highly conserved among all mitochondrial carriers, had a greatly reduced uncoupling activity. The two naturally occurring uncoupling protein 3 mutants, V9M and V102I, were similar to uncoupling protein 3L with respect to effects on the yeast growth and whole yeast O2 consumption. The R282C mutant had a reduced effect compared to uncoupling protein 3L. In summary, uncoupling protein 3S and the three mutants of uncoupling protein 3 appear to be functional proteins with biochemical activities similar to uncoupling protein 3L, although uncoupling protein 3S and the R282C mutant have a modestly reduced function.

Carrier Proteins↗
PubMed1999

Cloning and characterization of the 5' flanking region of the human uncoupling protein 3 (UCP3) gene.

Uncoupling protein 3 (UCP3), a member of the UCP family, mainly expressed in skeletal muscle could be responsible for thermogenesis in humans. Since little is known about its regulation, we studied the 5' flanking region of the human UCP3 (hUCP3) gene, which potentially contains the promoter sequences. We report the hUCP3 transcription initiation on a G located 764 nucleotides upstream the A contained in the first translated codon. Therefore, hUCP3 first exon has 669 bases of untranslated sequence. We also report the cloning and sequencing of seven kilobases from the gene 5' end and analyze the features of the potential proximal promoter. The MyoD family binding motif, called E-box, is the most abundant on this region. Other muscle-specific motives present in the potential proximal promoter include a MEF2 site as well as binding sequences for ubiquitous factors such as GC box and two CAAT boxes. Additionally, three putative peroxisome proliferator and one thyroid hormone response elements (PPRE and TRE, respectively) are found, which suggest a potential role for the peroxisome proliferator-activated receptor (PPAR) and thyroid hormone in human UCP3 gene expression. The description of the promoter region of the UCP3 gene will facilitate the elucidation of its transcriptional control.

Base Sequence↗
PubMed2000

Energy metabolism in uncoupling protein 3 gene knockout mice.

Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

Animals↗
PubMed1999

High-fat feeding reduced muscle uncoupling protein 3 expression in rats.

Uncoupling Protein 3 (UCP3), largely expressed in skeletal muscle, is modulated by cold, thyroid hormones, leptin, fasting-refeeding and exercise training among other factors in a tissue-specific manner. In brown adipose tissue, there is an increase in UCP3 levels after high-fat feeding and beta3-adrenergic agonist treatment. Controversial effects of these agents have been reported in skeletal muscle. The aim of this experimental trial was to evaluate the effect of high-fat feeding and beta3-adrenergic agent treatment on skeletal muscle UCP3 expression levels. Lean rats were fed a cafeteria diet for 30 days and found to have significantly higher fat stores and body weight than control rats at the end of the experimental period. When cafeteria-diet rats were daily i.p. injected with Tertatolol for 30 days; a decrease in total fat mass and body weight was found. Such an effect was not observed in fa/fa rats. Interestingly, gastrocnemius muscle UCP3 mRNA levels were significantly reduced in cafeteria-diet rats when compared to lean animals. Likewise, mitochondrial O2 consumption in gastrocnemius muscle was also significantly decreased (-31%) in cafeteria-diet rats as compared to the control group. It is suggested that the down-regulation of UCP3 gene expression together with the lower O2 consumption observed in high fat fed rats may be linked to lower fatty oxidation, which would promote triglyceride accumulation.

Adrenergic beta-Antagonists↗
PubMed2001

Uncoupling protein 3 biological activity.

The hypothesis that uncoupling protein 3 (UCP3) is an uncoupling protein involved in heat dissipation is not unequivocally supported. An update of in vitro, ex vivo and in vivo studies testing this hypothesis is presented. Data are provided showing that exercise induces a fatty acid-dependent increase in muscle UCP3 mRNA in humans. The proposed positive correlation between glycolytic capacity and UCP3 level in various muscle-fibre types in the mouse is reassessed. Finally, an association between an intronic polymorphism of UCP3 and adiposity is reported.

Animals↗
PubMed1999

Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes.

Uncoupling protein-1 (UCP1) dissipates the transmitochondrial proton gradient as heat. UCP2 and UCP3 are two recently discovered homologues that also have uncoupling activity and thus presumably have a role in energy homeostasis. We now report the genomic structure of murine UCP3 (7 exons) and UCP2 (8 exons). UCP3 is approximately 8 kilobases upstream of UCP2. An UCP3 variant mRNA, UCP3S, was also found and characterized. The effect of a high fat diet (45% versus 10%) on UCP3 and UCP2 mRNA levels was measured. Eating the 45% fat diet for eight weeks caused greater weight gain in AKR and C57BL/6J mice than in the obesity-resistant A/J mice. The high fat diet increased muscle UCP3 expression twofold in C57BL/6J animals. UCP2 expression increased slightly on the 45% fat diet in white adipose of AKR mice, but not in A/J or C57BL/6J mice. In skeletal muscle, UCP2 expression showed little variation with diet. Thus, UCP2 and UCP3 expression levels change in response to diet-induced obesity, but the changes are modest and depend on the tissue and genotype. The data suggest that it is not a reduction in UCP2 or UCP3 expression that causes obesity in the susceptible mice.

Adipose Tissue↗
PubMed2001

Insulin-like growth factor type 1 upregulates uncoupling protein 3.

In this study the expression of uncoupling protein 3 (UCP3) and its regulation by insulin-like growth factor 1 (IGF-I) and insulin in human neuroblastoma SH-SY5Y cells were characterized. Reverse transcriptase-PCR, Western blot, and immunofluorescence analysis showed that SH-SY5Y cells express UCP3 natively. IGF-I induced a time- and concentration-dependent induction of UCP3 protein reaching a twofold expression after 72 h with 10 nM IGF-I. Extremely high insulin concentrations (860 nM) and 10 nM trIGF-I, a truncated form of IGF-I with the same affinity for the IGF-I receptor as the full-length IGF-I, but with lower activity on the insulin receptor, also upregulated UCP3. We conclude that SH-SY5Y cells express UCP3 natively and that the expression is regulated by IGF-I via the IGF-I receptor.

Carrier Proteins↗
PubMed2001

Tissue-specific activity of lipoprotein lipase in skeletal muscle regulates the expression of uncoupling protein 3 in transgenic mouse models.

Uncoupling protein (UCP)-2 and UCP-3 are two recently discovered proteins similar to UCP-1, which regulates thermogenesis in brown adipose tissue (BAT). Whereas UCP-1 expression is restricted to BAT, UCP-2 is widely expressed. UCP-3 is found mainly in skeletal muscle and BAT. A large body of evidence exists that the expression of UCP-2 and UCP-3 in skeletal muscle of mice is regulated by feeding/fasting, and some studies have suggested that this effect might be caused by the changing concentration of plasma non-esterified fatty acids (NEFAs). In an attempt to determine whether the increased import of triacylglycerol-derived NEFAs can also affect UCP expression, we determined the mRNA levels of UCP-1, UCP-2 and UCP-3 in BAT and muscle of induced mutant mouse lines that overexpressed or lacked lipoprotein lipase (LPL) in these tissues. The expression levels of UCP-1 and UCP-2 in BAT and in skeletal and cardiac muscle respectively were not affected by variations in tissue LPL activities. In contrast, UCP-3 mRNA levels were induced 3.4-fold in mice with high levels of LPL in skeletal muscle, and down-regulated in mice that lacked LPL in skeletal muscle. The presence or absence of LPL in BAT had no effect on UCP-3 expression levels. The response of UCP-3 mRNA expression to variations in LPL activity in skeletal muscle was independent of the feeding status or of plasma NEFA concentrations. These findings indicated that NEFAs as lipolytic products of LPL-mediated triacylglycerol hydrolysis markedly affect UCP-3 expression and that increased LPL activities occurring during fasting in skeletal muscle contribute to the induction of UCP-3 expression by promoting the increased uptake of NEFAs. In addition, our results demonstrate that UCP-2 and UCP-3 are differentially regulated in response to LPL-mediated NEFA uptake in skeletal muscle of mice.

Adipose Tissue, Brown↗
PubMed1999

Assessment of uncoupling activity of uncoupling protein 3 using a yeast heterologous expression system.

Uncoupling protein 3L, uncoupling protein 1 and the mitochondrial oxoglutarate carrier were expressed in Saccharomyces cerevisae. Effects on different parameters related to the energy expenditure were studied. Both uncoupling protein 3L and uncoupling protein 1 reduced the growth rate by 49% and 32% and increased the whole yeast O2 consumption by 31% and 19%, respectively. In isolated mitochondria, uncoupling protein 1 increased the state 4 respiration by 1.8-fold, while uncoupling protein 3L increased the state 4 respiration by 1.2-fold. Interestingly, mutant uncoupling protein 1 carrying the H145Q and H147N mutations, previously shown to markedly decrease the H+ transport activity of uncoupling protein 1 when assessed using a proteoliposome system (Bienengraeber et al. (1998) Biochem. 37, 3-8), uncoupled the mitochondrial respiration to almost the same degree as wild-type uncoupling protein 1. Thus, absence of this histidine pair in uncoupling protein 2 and uncoupling protein 3 does not by itself rule out the possibility that these carriers have an uncoupling function. The oxoglutarate carrier had no effect on any of the studied parameters. In summary, a discordance exists between the magnitude of effects of uncoupling protein 3L and uncoupling protein 1 in whole yeast versus isolated mitochondria, with uncoupling protein 3L having greater effects in whole yeast and a smaller effect on the state 4 respiration in isolated mitochondria. These findings suggest that uncoupling protein 3L, like uncoupling protein 1, has an uncoupling activity. However, the mechanism of action and/or regulation of the activity of uncoupling protein 3L is likely to be different.

Animals↗
PubMed2001

Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes.

Uncoupling protein 3 (UCP3), which uncouples electron transport from ATP synthesis, is expressed at high levels in the skeletal muscle, an important organ in glucose and lipid metabolism. Because several reports proposed that fatty acids induced UCP3 gene expression in skeletal muscle in vivo, in the present study we examined the regulation of UCP3 gene expression by various fatty acids using L6 myotubes. UCP3 gene expression was increased in L6 myotubes by various fatty acids or by alpha-bromopalmitate, a nonmetabolized derivative of palmitic acid. Because fatty acids are also known as agonists for PPARs, we examined the involvement of PPARs in the regulation of the UCP3 gene expression. L-165041, a PPAR delta agonist, increased UCP3 gene expression in L6 myotubes, whereas neither Wy 14,643, a PPAR alpha agonist, nor Pioglitazone, a PPAR gamma agonist, increased it. Therefore, we conclude that UCP3 gene expression is increased by the activation of PPAR delta in L6 myotubes and postulate that PPAR delta mediates at least some part of the increased UCP3 gene expression by fatty acids in skeletal muscle in vivo.

Animals↗
PubMed1999

Endogenous mutations in human uncoupling protein 3 alter its functional properties.

Human uncoupling protein (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative phosphorylation and is a candidate gene for obesity. Expression of native human UCP3 mutations in yeast showed complete loss (R70W), significant reduction (R143X), or no effect (V102I and IVS6+1G > A) on the uncoupling activity of UCP3. It is concluded that certain mutations in UCP3 alter its functional impact on membrane potential (deltaphi), possibly conferring susceptibility to develop metabolic diseases.

Carrier Proteins↗
PubMed2001

Mitochondrial uncoupling protein 3 (UCP3) in skeletal muscle.

Mitochondrial uncoupling protein (UCP), mitochondrial transporters, function as a proton channel and increase thermogenesis. UCP1 is expressed in brown adipose tissues (BAT), UCP2 is widely expressed in multiple tissues, while UCP3 is expressed in skeletal muscle. Thus, UCPs, especially UCP3, in skeletal muscles is a good candidates for prevention of obesity and diabetes. However, the role of UCP3 in skeletal muscle for energy expenditure and obesity has been controversial. There is some evidence that the UCP3 is possibly regulated by energy substrate, such as lipid and glucose. These observations suggest that increased energy substrate entry in muscle results in an increase in UCP3 expression which leads to an increase in energy expenditure.

Animals↗
PubMed1999

Uncoupling protein 3: its possible biological role and mode of regulation in rodents and humans.

The recently discovered uncoupling protein 3 (UCP3) is highly homologous to the mitochondrial inner membrane protein UCP1, which generates heat by uncoupling the respiratory chain from oxidative phosphorylation. The thermogenic function of UCP1 protects against cold and regulates the energy balance in rodents. We review in vitro studies investigating the uncoupling activity of UCP3 and in vivo studies, which address UCP3 gene expression in brown adipose tissue and skeletal muscle under various metabolic conditions. The data presented are, for the most, consistent with an uncoupling role for UCP3 in regulatory thermogenesis. We also discuss mediators of UCP3 regulation and propose a potential role for intracellular fatty acids in the mechanism of UCP3 modulation. Finally, we hypothesize a role for UCP3 in the metabolic adaptation of the mitochondria to the degradation of fatty acids.

Animals↗
PubMed2001

Uncoupling protein 3 and fatty acid metabolism.

A role for uncoupling protein (UCP) 3 in fatty acid metabolism is reviewed within the context of our proposal, first put forward in 1998, that this homologue of UCP1 may be involved in the regulation of lipids as fuel substrate rather than in the mediation of thermogenesis. Since then, the demonstrations of muscle-type differences in UCP3 gene regulation in response to dietary manipulations (starvation, high-fat feeding) or to pharmacological interferences with the flux of lipid substrates between adipose-tissue stores and skeletal-muscle mitochondrial oxidation are all in accord with this proposed role for UCP3 in regulating lipids as fuel substrate. However, given the current limitations of gene-knockout technology for evaluating/interpreting the functional importance of genes encoding mitochondrial membrane proteins, the transition from 'associative' to 'cause-and-effect' evidence for a physiological role of UCP3 in regulating fatty acid metabolism will have to await the development of assays that are sensitive to changes in UCP3 activity. Furthermore, in evaluating the physiological regulators of UCP3, the available evidence points to the existence of adipose-derived factor(s) which, independently of circulating levels of free fatty acids, initiates events leading to the transcription of genes encoding UCP3 and key enzymes of lipid oxidation in the fast glycolytic or fast oxidative-glycolytic muscles, i.e. in the bulk of the skeletal-muscle mass. It is proposed that in tissues where UCP3 co-exists with UCP2 (skeletal muscle, brown adipose tissue, heart) they may act in concert in the overall regulation of lipid oxidation, concomitant to the prevention of lipid-induced oxidative damage.

Adipose Tissue↗
PubMed1998

Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.

Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.

Alternative Splicing↗
PubMed1998

Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting.

The newly described uncoupling protein 3 (UCP3) may make an important contribution to thermogenesis in humans because of its high level of expression in skeletal muscle. Contrary to expectations, fasting, a condition that reduces resting energy expenditure, has been reported to increase UCP3 expression in muscle. We have confirmed that a 10-fold increase in UCP3 mRNA levels occurs in rat quadriceps muscle between 12 and 24 h of food removal. A less consistent twofold increase in muscle UCP2 mRNA levels was observed in animals fasted for up to 72 h. Administration of recombinant leptin to prevent a fall in circulating leptin levels did not eliminate the fasting-induced increase in quadriceps UCP3 expression. Administration of a high dose of glucocorticoid to fed animals to mimic the increase in corticosterone induced by fasting did not reproduce the increase in UCP3 expression observed in fasted animals. In contrast, elevation of circulating free fatty acid levels in fed animals by Intralipid plus heparin infusion caused significant increases in the UCP3/actin mRNA ratio compared with saline-infused fed controls in both extensor digitorum longus (2.01 +/- 0.34 vs. 0.68 +/- 0.11, P = 0.002) and soleus muscles (0.31 +/- 0.07 vs. 0.09 +/- 0.02, P = 0.014). We conclude that free fatty acids are a potential mediator of the increase in muscle UCP3 expression that occurs during fasting. This seemingly paradoxical induction of UCP3 may be linked to the use of free fatty acid as a fuel rather than an increased need of the organism to dissipate energy.

Animals↗
PubMed1999

Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis.

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.

Alternative Splicing↗