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PubMed2005

Linkage and association analyses of the UCP3 gene with obesity phenotypes in Caucasian families.

Uncoupling protein 3 (UCP3) uncouples ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting the efficiency of energy metabolism. Genetic variations in the UCP3 gene have been conceived to affect body weight in the general population. In this study, using the quantitative transmission disequilibrium test (QTDT), we assessed linkage and association between the UCP3 gene and obesity phenotypes in a large sample of 1,873 subjects from 405 United States Caucasian nuclear families. Obesity phenotypes tested include body mass index (BMI), fat mass, percent fat mass (PFM), and lean mass, with the latter three measured by dual-energy X-ray absorptiometry. We first selected five single nucleotide polymorphisms (SNPs) and then analyzed three highly polymorphic ones, namely, -55 C/T (promoter), Tyr99Tyr (exon 3), and Tyr210Tyr (exon 5), in the total sample. Significant linkage disequilibria (0.392 <or= D' <or= 0.940, P < 0.0001) were observed between pairs of SNPs. In single-locus analyses, we found statistically significant association (P = 0.034) and linkage (P = 0.031) between -55 C/T and BMI. This polymorphism explains 2.29% of BMI variation, and subjects carrying the T allele had an average of 3.5% lower BMI than those without it (P = 0.003). In haplotype analyses, we also observed evidence of linkage (P = 0.002) and association (P = 0.035) with BMI. In summary, our results suggest that UCP3 gene polymorphisms may contribute to BMI variation in this Caucasian population.

Alleles↗
PubMed2004

The -55 C/T polymorphism within the UCP3 gene and performance during the South African Ironman Triathlon.

Uncoupling protein 3 is believed to be involved in total body energy expenditure, including the regulation of fat and glucose metabolism. These biochemical processes may distinguish top ultra-endurance triathletes from slower competitors. The aim of this study was to determine whether the uncoupling protein 3 gene is associated with the performance capacity of ultra-endurance Ironman triathletes. Two triathlete groups consisting of the 89 fastest and 89 slowest Caucasian, male triathletes who completed either the 2000 or 2001 South African Ironman triathlon events were genotyped for the -55 C/T polymorphism within the uncoupling protein 3 gene. A control group consisting of 92 Caucasian males who had not trained for or participated in an ultra-endurance athletic event was also genotyped. There was no significant difference in the genotype (CC, CT and TT) frequency distribution of the -55 C/T polymorphism within the uncoupling protein 3 gene between the fast triathlete, slow triathlete and control groups. In addition, no significant differences were observed between the frequencies of the C and T alleles between the three groups. The two triathlete groups were combined and grouped according to their genotype. No particular genotype or allele was associated with the time taken by the triathletes to complete the entire triathlon, or either the swim, cycle or run legs of the event. Thus no association was found between the -55 C/T polymorphism within the uncoupling protein 3 gene and the ultra-endurance performance of triathletes who completed either the 2000 or 2001 South African Ironman triathlons.

Alleles↗
PubMed2004

[Changes in uncoupling protein-2, 3 mRNA expression in the scalded rats after escharectomy at different post scalding stages].

OBJECTIVE: To investigate the expression of uncoupling protein (UCP)-2, 3 mRNA in skeletal muscle of the scalded rats after escharectomy at different post scalding stages. METHODS: One hundred and twenty Wistar rats were employed in the study, in which 8 served as normal control (C) and 112 were subjected to 30% TBSA 3rd degree scalding and then again, divided into 4 groups. The rats in A group were sacrificed on 8th, 24th, 96th, 120th and 168th post scalding hours (PSHs) without escharectomy. The rats in B group underwent escharectomy at 8 PSH, and those in C group underwent escharectomy at 24 PSH. All the rats in both groups were sacrificed on 96, 120 and 168 PSHs after escharectomy, Escharectomy was performed at 96 PSH in rats of D group, and they were sacrificed on 120 and 168 PSHs after escharectomy. The serum levels of leptin and TNFalpha, and the expression level of UCP2 mRNA were determined at all time points in all groups of rats. RESULTS: (1) The serum levels of leptin in A group were obviously lower than that in C group (P < 0.01) during 24 approximately 168 PSHs, while those in B, C and D groups were much higher than those in A group (P < 0.01) during 24 approximately 168 PSH. (2) The serum TNFalpha levels in A group at all time points were higher than that in control group, while that in B group at all time points were lower than that in A group (P < 0.05 or 0.01), and that in C group at 168 PSH was lower than that in A group (P < 0.05). (3) The UCP2 mRNA expression in skeletal muscle in A group was increased evidently since 8 PSH (P < 0.01), peaking at 24 PSH and lowering thereafter, while that in B and C groups at 168PSH was significantly lower than that in A group at the same time points (0.32 and 0.35 vs 0.71, P < 0.05). The trend of the change in UCP3 mRNA expression in skeletal muscle was similar to that of UCP2. CONCLUSION: The postburn up-regulation of UCP mRNA expression might play important roles in the increase of metabolic rate. Escharectomy during shock stage could lower down the expression of UCP2 and UCP3 mRNA expression, and it could be beneficial by lowering metabolic rate.

Animals↗
PubMed2005

Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle.

Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation/inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine/palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for beta oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor alpha (PPARalpha), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an alpha-adrenergic blocking agent, prevents the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced decrease of skeletal muscle malonyl-CoA. Thus, the sympathetic nervous system is implicated in the transmission of the "malonyl-CoA signal" from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPARalpha is the concomitant increase in the expression of PGC1alpha, transcriptional coactivator of the UCP3 and PPARalpha-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure.

4-Butyrolactone↗
PubMed2005

Thyroid-hormone effects on putative biochemical pathways involved in UCP3 activation in rat skeletal muscle mitochondria.

In vitro, uncoupling protein 3 (UCP3)-mediated uncoupling requires cofactors [e.g., superoxides, coenzyme Q (CoQ) and fatty acids (FA)] or their derivatives, but it is not yet clear whether or how such activators interact with each other under given physiological or pathophysiological conditions. Since triiodothyronine (T3) stimulates lipid metabolism, UCP3 expression and mitochondrial uncoupling, we examined its effects on some biochemical pathways that may underlie UCP3-mediated uncoupling. T3-treated rats (Hyper) showed increased mitochondrial lipid-oxidation rates, increased expression and activity of enzymes involved in lipid handling and increased mitochondrial superoxide production and CoQ levels. Despite the higher mitochondrial superoxide production in Hyper, euthyroid and hyperthyroid mitochondria showed no differences in proton-conductance when FA were chelated by bovine serum albumin. However, mitochondria from Hyper showed a palmitoyl-carnitine-induced and GDP-inhibited increased proton-conductance in the presence of carboxyatractylate. We suggest that T3 stimulates the UCP3 activity in vivo by affecting the complex network of biochemical pathways underlying the UCP3 activation.

Animals↗
PubMed2000

Uncoupling proteins 2 and 3 interact with members of the 14.3.3 family.

Uncoupling proteins (UCPs) are members of the superfamily of the mitochondrial anion carrier proteins (MATP). Localized in the inner membrane of the organelle, they are postulated to be regulators of mitochondrial uncoupling. UCP2 and 3 may play an important role in the regulation of thermogenesis and, thus, on the resting metabolic rate in humans. To identify interacting proteins that may be involved in the regulation of the activity of UCPs, the yeast two-hybrid system was applied. Segments of hUCP2 containing the hydrophilic loops facing the intermembrane space, or combinations of these, were used to screen an adipocyte activation domain (AD) fusion library. The 14.3.3 protein isoforms theta, beta, zeta were identified as possible interacting partners of hUCP2. Screening of a human skeletal muscle AD fusion library, on the other hand, yielded several clones all of them encoding the gamma isoform of the 14.3.3 family. Mapping experiments further revealed that all these 14.3.3 proteins interact specifically with the C-terminal intermembrane space domain of both hUCP2 and hUCP3 whereas no interactions could be detected with the C-terminal part of hUCP1. Direct interaction between UCP3 and 14.3.3 theta could be demonstrated after in vitro translation by coimmunoprecipitation. When coexpressed in a heterologous yeast system, 14.3.3 proteins potentiated the inhibitory effect of UCP3 overexpression on cell growth. These findings suggest that 14.3.3 proteins could be involved in the targeting of UCPs to the mitochondria.

14-3-3 Proteins↗
PubMed2003

Sugars: hedonic aspects, neuroregulation, and energy balance.

The prevalence of obesity has increased dramatically in recent years in the United States, with similar patterns seen in several other countries. Although there are several potential explanations for this dramatic increase in obesity, dietary influences are a contributing factor. An inverse correlation between dietary sugar intake and body mass index has been reported, suggesting beneficial effects of carbohydrate intake on body mass index. In this review we discuss how sugars interact with regulatory neurochemicals in the brain to affect both energy intake and energy expenditure. These neurochemicals appear to be involved in dietary selection, and sugars and palatable substances affect neurochemical changes in the brain. For example, rats that drink sucrose solutions for 3 wk have major changes in neuronal activity in the limbic area of the brain, a region involved in pleasure and other emotions. We also investigate the relations between sucrose (and other sweet substances), drugs of abuse, and the mesolimbic dopaminergic system. The presence of sucrose in an animal's cage can affect the animals desire to self-administer drugs of abuse. Also, an animal's level of sucrose preference can predict its desire to self-administer cocaine. Such data suggest a relation between sweet taste and drug reward, although the relevance to humans is unclear. Finally, we address the influence of sugar on body weight control. For example, sucrose feeding for 2 wk decreases the efficiency of energy utilization and increases gene expression of uncoupling protein 3 in muscle, suggesting that sucrose may influence uncoupling protein 3 activity and contribute to changes in metabolic efficiency and thus regulation of body weight.

Animals↗
PubMed2003

UCP3 protein regulation in human skeletal muscle fibre types I, IIa and IIx is dependent on exercise intensity.

It has been proposed that mitochondrial uncoupling protein 3 (UCP3) behaves as an uncoupler of oxidative phosphorylation. In a cross-sectional study, UCP3 protein levels were found to be lower in all fibre types of endurance-trained cyclists as compared to healthy controls. This decrease was greatest in the type I oxidative fibres, and it was hypothesised that this may be due to the preferential recruitment of these fibres during endurance training. To test this hypothesis, we compared the effects of 6 weeks of endurance (ETr) and sprint (STr) running training on UCP3 mRNA expression and fibre-type protein content using real-time PCR and immunofluorescence techniques, respectively. UCP3 mRNA and protein levels were downregulated similarly in ETr and STr (UCP3 mRNA: by 65 and 50%, respectively; protein: by 30 and 27%, respectively). ETr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 54, 29 and 16%, respectively. STr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 24, 31 and 26%, respectively. The fibre-type reductions in UCP3 due to ETr, but not STr, were significantly different from each other, with the effect being greater in type I than in type IIa, and in type IIa than in type IIx fibres. As a result, compared to STr, ETr reduced UCP3 expression significantly more in fibre type I and significantly less in fibre types IIx. This suggests that the more a fibre is recruited, the more it adapts to training by a decrease in its UCP3 expression. In addition, the more a fibre type depends on fatty acid beta oxidation and oxidative phosphorylation, the more it responds to ETr by a decrease in its UCP3 content.

Adult↗
PubMed2005

Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise.

In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, 9 male subjects (aged 22-27) completed 75 minutes of cycling exercise at 75% Vo2 max on 2 occasions, consuming either a high-carbohydrate (HC) or low-carbohydrate (LC) diet during the subsequent 24 hours of recovery. Nuclei were isolated and tissue frozen from vastus lateralis muscle biopsies obtained before exercise and 2, 5, 8, and 24 hours after exercise. Muscle glycogen was restored to near resting levels within 5 hours in the HC trial, but remained depressed through 24 hours in the LC trial. During the 2- to 8-hour recovery period, leg glucose uptake was 5- to 15-fold higher with HC ingestion, whereas arterial plasma free fatty acid levels were approximately 3- to 7-fold higher with LC ingestion. Exercise increased (P < .05) transcription and/or mRNA content of the pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, carnitine palmitoyltransferase I, hexokinase II, peroxisome proliferator activated receptor gamma coactivator-1 alpha, and peroxisome proliferator activated receptor alpha. Providing HC during recovery reversed the activation of pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, and carnitine palmitoyltransferase I within 5 to 8 hours after exercise, whereas providing LC during recovery elicited a sustained/enhanced increase in activation of these genes through 8 to 24 hours of recovery. These findings provide evidence that factors associated with substrate availability and/or cellular metabolic recovery (eg, muscle glycogen restoration) influence the transcriptional regulation of metabolic genes in skeletal muscle of humans during recovery from exercise.

Adult↗
PubMed2002

[Effect of iron on the expression of uncoupling protein 2, 3 gene of obese rat].

In order to study the effect of iron on the expression of UCP2 in white fat and UCP3 in muscle in obese rats, a reverse transcription polymerase chain reaction (RT-PCR) technique is used to measure the expression of UCP2 and UCP3 mRNA. The results show: (1) Adequate iron improves the level of thyroid hormone in blood serum; (2) the body fat content of obese rat in 5, 10, and 20 times of iron supplement groups is lower than that of obese rats in normal iron supplement group; (3) the UCP2 and UCP3 mRNA expression of iron-deficient obese rats is low in iron-deficient obese rats; (4) iron supplement enhances the level of UCP3 mRNA expression in muscle and the level of UCP3 mRNA is the highest in the 5 times iron supplement group and about 2 times of that of basic diet group. However, there is no effect on the UCP2 mRNA expression induced by high energy diet. It suggested that adequate iron can improve the level of serum thyroid hormone, induce the UCP3 mRNA expression in muscle and mobilize fat to produce heat, but had no effect on UCP2 mRNA in white fat of obese rat.

Animals↗
PubMed2001

Beta 3-adrenergic agonist up-regulates uncoupling proteins 2 and 3 in skeletal muscle of the mouse.

Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective beta3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8-4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the beta3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of beta3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.

Adipose Tissue, Brown↗
PubMed1999

Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects.

AIMS/HYPOTHESIS: The regulation of uncoupling protein 2 and uncoupling protein 3 gene expression in skeletal muscle has recently been the focus of intense interest. Our aim was to determine expression of uncoupling protein 2 and 3 in skeletal muscle from tetraplegic subjects, a condition representing profound muscle inactivity. Thereafter we determined whether exercise training would modify expression of these genes in skeletal muscle. METHODS: mRNA expression of uncoupling protein 2 and 3 was determined using quantitative reverse transcription-polymerase chain-reaction. RESULTS: Expression of uncoupling protein 2 and 3 mRNA was increased in skeletal muscle from tetraplegic compared with able-bodied subjects (3.7-fold p < 0.01 and 4.1-fold, p < 0.05, respectively). A subgroup of four tetraplegic subjects underwent an 8-week exercise programme consisting of electrically-stimulated leg cycling (ESLC, 7 ESLC sessions/week). This training protocol leads to increases in whole body insulin-stimulated glucose uptake and expression of genes involved in glucose metabolism in skeletal muscle from tetraplegic subjects. After ESLC training, uncoupling protein 2 expression was reduced by 62% and was similar to that in able-bodied people. Similarly, ESLC training was associated with a reduction of uncoupling protein 3 expression in skeletal muscle from three of four tetraplegic subjects, however, post-exercise levels remained increased compared with able-bodied subjects. CONCLUSION/INTERPRETATION: Tetraplegia is associated with increased mRNA expression of uncoupling protein 2 and 3 in skeletal muscle. Exercise training leads to normalisation of uncoupling protein 2 expression in tetraplegic subjects. Muscle disuse and physical activity appear to be powerful regulators of uncoupling protein 2 and 3 expression in human skeletal muscle.

Adult↗
PubMed2002

Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.

Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR alpha knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR alpha target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma. In both human and rodent myocytes, the highly selective PPAR delta agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR alpha agonist GW647. These results show redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha.

Animals↗
PubMed2006

The relationships among mitochondrial uncoupling protein 2 and 3 expression, mitochondrial deoxyribonucleic acid single nucleotide polymorphisms, and residual feed intake in Angus steers.

The objective of this study was to determine the relationships of uncoupling protein 2 and 3 expression, SNP of mitochondrial DNA, and residual feed intake (RFI) in Angus steers selected to have high or low RFI. Individual feed intake was measured via the GrowSafe feed intake system over a 3-mo period and used to calculate RFI, a measure of efficiency. Based on these calculations, 6 low- (average RFI = -1.57 kg) and 6 high- (average RFI = 1.66 kg) RFI steers were selected for further study. Blood was collected via jugular venipuncture 1 wk before slaughter for the isolation of mitochondrial DNA. The steers were then killed to collect LM for the measurement of uncoupling protein 2 and 3 mRNA and protein expression. Protein and mRNA expression of uncoupling protein 2 and 3 were determined by Western blotting and quantitative PCR, respectively. To determine SNP of mitochondrial DNA, total DNA was isolated from blood via standard phenol/chloroform extraction; fragments were amplified with PCR and sequenced with an automated nucleotide sequencer. Average daily gain and carcass composition were not different (P > 0.13) between the high- and low-RFI steers; however, ADFI by the high-RFI animals was 3.77 kg greater (P < 0.001) than the low-RFI animals. No difference (P > 0.55) was observed between the high- and low-RFI animals in their expression of uncoupling protein 2 or 3 mRNA or protein. On average 9.8 and 8.9 polymorphisms were found per mitochondrial genome for the low- and high-RFI steers, respectively. None of these polymorphisms were related to RFI. It seems that the expression of uncoupling protein 2 and 3 and mitochondrial DNA sequence are not related to RFI status.

Animal Feed↗
PubMed2007

UCP2 and 3 deletion screening and distribution in 15 pig breeds.

The uncoupling protein family is a mitochondrial anion carrier family. It plays an important role in the biological traits of animal body weight, basal metabolic rate and energy conversion. Using PCR and PCR-SSCP, we scanned the porcine uncoupling protein 2 gene (UCP2) and uncoupling protein 3 gene (UCP3) and found seven deletion sites, three in UCP2 and four in UCP3. The deletions in 15 pig breeds showed that deletion influenced weight. The genotype compounding of seven deletion sites in 15 pig breeds had significant effects on performance traits of the pig, such as body weight. We predicted the potential protein factor binding sites using the transcription factor analysis tool TFSearch version 1.3 online. Two deletions (1830 nt and 3219 nt) in UCP3 were found to change the transcriptional factor sites. The 16 bp deletion in 1830 nt added a SP1 site and a 6 bp deletion in 3219 nt removed two MZF1 sites. Seven deletion polymorphisms were covered in introns of linkage genes of UCP2 and UCP3, showing that UCPs have conservation and genetic reliability.

Animals↗
PubMed2002

UCP3 protein expression is lower in type I, IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects.

Uncoupling protein 3 (UCP3) is a muscle mitochondrial protein believed to uncouple the respiratory chain, producing heat and reducing aerobic ATP production. Our aim was to quantify and compare the UCP3 protein levels in type I, IIa and IIx skeletal muscle fibers of endurance-trained (Tr) and healthy untrained (UTr) individuals. UCP3 protein content was quantified using Western blot and immunofluorescence. Skeletal muscle fiber type was determined by both an enzymatic ATPase stain and immunofluorescence. UCP3 protein expression measured in skeletal muscle biopsies was 46% lower ( P=0.01) in the Tr compared to the UTr group. UCP3 protein expression in the different muscle fibers was expressed as follows; IIx>IIa>I in the fibers for both groups ( P<0.0167) but was lower in all fiber types of the Tr when compared to the UTr subjects ( P<0.001). Our results show that training status did not change the skeletal muscle fiber hierarchical UCP3 protein expression in the different fiber types. However, it affected UCP3 content more in type I and type IIa than in the type IIx muscle fibers. We suggest that this decrease may be in relation to the relative improvement in the antioxidant defense systems of the skeletal muscle fibers and that it might, as a consequence, participate in the training induced improvement in mechanical efficiency.

Adult↗
PubMed2003

Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle.

Mitochondrial proteins such as uncoupling protein 3 (UCP3) and adenine nucleotide translocase (ANT) may mediate back-leakage of protons and serve as uncouplers of oxidative phosphorylation. We hypothesized that UCP3 and ANT increase after prolonged exercise and/or endurance training, resulting in increased uncoupled respiration (UCR). Subjects were investigated with muscle biopsies before and after acute exercise (75 min of cycling at 70% of .VO2peak) or 6 weeks endurance training. Mitochondria were isolated and respiration measured in the absence (UCR or state 4) and presence of ADP (coupled respiration or state 3). Protein expression of UCP3 and ANT was measured with Western blotting. After endurance training, .VO2peak, citrate synthase activity (CS), state 3 respiration and ANT increased by 24, 47, 40 and 95%, respectively (all P < 0.05), whereas UCP3 remained unchanged. When expressed per unit of CS (a marker of mitochondrial volume) UCP3 and UCR decreased by 54% and 18%(P < 0.05). CS increased by 43% after acute exercise and remained elevated after 3 h of recovery (P < 0.05), whereas the other muscle parameters remained unchanged. An intriguing finding was that acute exercise reversibly enhanced the capacity of mitochondria to accumulate Ca2+(P < 0.05) before opening of permeability transition pores. In conclusion, UCP3 protein and UCR decrease after endurance training when related to mitochondrial volume. These changes may prevent excessive basal thermogenesis. Acute exercise enhances mitochondrial resistance to Ca2+ overload but does not influence UCR or protein expression of UCP3 and ANT. The increased Ca2+ resistance may prevent mitochondrial degradation and the mechanism needs to be further explored.

Adenosine Diphosphate↗
PubMed2005

Towards comprehension of the physiological role of UCP3.

Thyroid hormones have long been known to stimulate energy expenditure partly via loss of metabolic efficiency. The mechanism underlying the loss in metabolic efficiency observed, however, is not yet understood. An important candidate gene responsible for thyroid hormone induced thermogenesis was identified in 1997 with the discovery of skeletal muscle-uncoupling protein 3 (UCP3), a protein with approximately 60 % homology to the brown adipose tissue uncoupling protein 1 (UCP1). This short review summarizes our presentation held at the 'Thyroid and Sports' meeting; it does not aim to provide a concise overview of the available literature at this topic. Although induction of the UCP3 gene and increased protein expression during hyperthyroidism has been shown, there are no convincing data that increased UCP3 levels account for the increase in thermogenesis in the hyperthyroid state in humans. In contrast to cell and animal studies using ectopic overexpression of UCP3 as a model, induction of UCP3 in humans does not result in any apparent mitochondrial uncoupling. Hence, the primary physiological role of UCP3 may not be mitochondrial uncoupling, but uncoupling may occur as a side effect of a more pivotal role played by UCP3. Recently, UCP3 has been hypothesized to export fatty acid anions and/or lipid peroxides away from the mitochondrial matrix to prevent mitochondria from the harmful effects of peroxidized lipids. The present review aims to provide an overview of studies testing the feasibility of this unconventional function of UCP3.

Adipose Tissue↗