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PubMed2000

Defective dietary induction of uncoupling protein 3 in skeletal muscle of obesity-prone rats.

OBJECTIVE: The goal of this study was to determine whether differential induction of skeletal muscle uncoupling protein 3 (UCP3) contributes to the development of diet-induced obesity (DIO) or resistance to the development of obesity (DR) when rats are placed on a moderate fat (31%) high energy (HE) diet. RESEARCH METHODS AND PROCEDURES: Gastrocnemius muscle was obtained from Sprague-Dawley rats that were identified as DIO-prone (n = 5) or DR (n = 5) on the basis of urinary norepinephrine excretion while consuming a chow diet. Muscle was also obtained from animals in the top tertile of weight gain (DIOHE, n = 5) and the bottom tertile of weight gain (DRHE, n = 5) after 2 weeks on the HE diet. UCP3 and actin mRNA levels were measured in all muscle samples by Northern analysis. To distinguish the effect of dietary energy content from the effect of obesity itself, we studied additional DIO and DR animals that had been returned to a chow diet for 10 weeks after consuming a HE diet for 10 weeks. RESULTS: The muscle UCP3/actin mRNA ratio in animals that resisted the development of obesity during 2 weeks on the HE diet was 3-fold higher than in the other groups (DRHE = 3.24 +/- 0.83, DIOHE = 0.91 +/- 0.20, DIO-prone = 0.72 +/- 0.15, DR = 0.63 +/- 0.15; p = 0.002). However, there was no difference in muscle UCP3/actin mRNA ratios between DIO animals and DR animals that had been fed the HE diet for 10 weeks and then returned to either an ad libitum chow diet for 10 weeks (DIO = 13.8 +/- 3.53, DR = 11.1 +/- 3.43, p = NS) or to a restricted chow diet for 10 weeks (DIO = 11.0 +/- 2.85, DR = 10.6 +/- 2.20, p = NS) despite significantly greater body weight of the DIO animals. DISCUSSION: DR animals may initially resist weight gain when placed on a HE diet through a greater induction of muscle UCP3. This induction is transient and is related more closely to dietary fat content than to body fat stores. DIO animals show no initial induction of muscle UCP3, which may contribute to their increased metabolic efficiency soon after exposure to a HE diet.

Actins↗
PubMed2003

[The effect of dietary calcium on the expression of uncoupling protein 3 gene in skeletal muscle of rat fed with high fat diet].

In order to study the effects of dietary calcium on the expression of uncoupling protein 3(UCP3) in skeletal muscle of Wistar rat fed with high fat diet, 54 male Wistar rats were randomly divided into 6 groups: Group A was fed with basic diet(0.5% calcium), Group B was fed with high fat low calcium diet(0.08% calcium), Group C was fed with high fat normal calcium diet(0.5% calcium), Group D and E was fed with high fat high calcium diet(1% and 1.5% calcium respectively), Group F was fed with high fat high calcium diet (1.5% calcium) supplemented with vitamin D(600 IU%). Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the level of UCP3 mRNA. The results showed that the body weight and fat content in group C were significantly higher than those in group A. However, the body weight gain in groups of D, E, and F was less than those in group C. The serum insulin in group C increased significantly compared with that in groups of A, D, E and F(P < 0.05), but there was no significant difference in blood glucose among all groups. Compared with group A, the level of serum leptin increased significantly in group C(P < 0.05) and increased slightly in groups D, E and F (P > 0.05). The level of serum FT3 in groups D, E and F increased significantly compared with that of group A, B and C(P < 0.05), but there was no significant difference in FT4 among all groups(P > 0.05). Compared with group A, the expression of UCP3 mRNA decreased in skeletal muscle in group C, while UCP3 mRNA increased in groups D, E and F compared with that of group C. In conclusion, dietary calcium may not only reduce the body weight gain induced by high fat diet, and improve hyperinsulinemia, but also may enhance the expression of UCP3 mRNA in skeletal muscle by increasing the serum level of leptin and FT3 which may play the role in the prevention of obesity.

Animals↗
PubMed2004

Production of endogenous matrix superoxide from mitochondrial complex I leads to activation of uncoupling protein 3.

Superoxide generated using exogenous xanthine oxidase indirectly activates an uncoupling protein (UCP)-mediated proton conductance of the mitochondrial inner membrane. We investigated whether endogenous mitochondrial superoxide production could also activate proton conductance. When respiring on succinate, rat skeletal muscle mitochondria produced large amounts of matrix superoxide. Addition of GDP to inhibit UCP3 markedly inhibited proton conductance and increased superoxide production. Both superoxide production and the GDP-sensitive proton conductance were suppressed by rotenone plus an antioxidant. Thus, endogenous superoxide can activate the proton conductance of UCP3, which in turn limits mitochondrial superoxide production. These observations provide a departure point for studies under more physiological conditions.

Animals↗
PubMed2006

Uncoupling protein 3 expression and intramyocellular lipid accumulation by NMR following local burn trauma.

Burn trauma is a clinical condition accompanied by muscle wasting that severely impedes rehabilitation in burn survivors. Mitochondrial uncoupling protein 3 (UCP3) is uniformly expressed in myoskeletal mitochondria and its expression has been found to increase in other clinical syndromes that, like burn trauma, are associated with muscle wasting (e.g., starvation, fasting, cancer, sepsis). The aim of this study was to explore the effects of burn trauma on UCP3 expression, intramyocellular lipids, and plasma-free fatty acids. Mice were studied at 6 h, 1 d and 3 d after nonlethal hindlimb burn trauma. Intramyocellular lipids in hindlimb skeletal muscle samples collected from burned and normal mice were measured using 1H NMR spectroscopy on a Bruker 14.1 Tesla spectrometer at 4 degrees C. UCP3 mRNA and protein levels were also measured in these samples. Plasma-free fatty acids were measured in burned and normal mice. Local burn trauma was found to result in: 1) upregulation of UCP3 mRNA and protein expression in hindlimb myoskeletal mitochondria by 6 h postburn; 2) increased intramyocellular lipids; and 3) increased plasma-free fatty acids. Our findings show that the increase in UCP3 after burn trauma may be linked to burn-induced alterations in lipid metabolism. Such a link could reveal novel insights into how processes related to energy metabolism are controlled in burn and suggest that induction of UCP3 by burn in skeletal muscle is protective by either activating cellular redox signaling and/or mitochondrial uncoupling.

Animals↗
PubMed2001

High-fat diet feeding elevates skeletal muscle uncoupling protein 3 levels but not its activity in rats.

OBJECTIVE: The objective of this study is to test the impact of high-fat diet (HFD) feeding on skeletal muscle (SM) uncoupling protein 3 (UCP3) expression and its association with mitochondrial ion permeability and whole-body energy homeostasis. RESEARCH METHODS AND PROCEDURES: Sprague-Dawley rats were fed ad libitum either a HFD (60% of energy from fat, n = 6) or a low-fat diet (12% of energy from fat, n = 6) for 4 weeks. Twenty-four-hour energy expenditure was measured by indirect calorimetry in the last week of the dietary treatment. Blood samples were collected for plasma leptin and free fatty acid assays, and mitochondria were isolated from hindlimb SM for subsequent determinations of UCP3 levels and mitochondrial ion permeability. RESULTS: Plasma leptin levels were higher in rats fed the HFD despite the same body weight in two groups. The same dietary treatment also rendered a 2-fold increase in plasma free fatty acid and SM UCP3 protein levels (Western blot) compared with the group fed the low-fat diet. However, the elevated UCP3 protein levels did not correlate with mitochondrial swelling rates, a measure of mitochondrial chloride, and proton permeability, or with 24-hour energy expenditure. DISCUSSION: The high correlation between the levels of plasma free fatty acid levels and SM UCP3 suggests that circulating free fatty acid may play an important role in UCP3 expression during the HFD feeding. However, the dissociation between the UCP3 protein levels and 24-hour energy expenditure as well as mitochondrial ion permeability suggests that mitochondrial proton leak mediated by muscle UCP3 may not be a major contributor in energy balance in HFD feeding, and other regulatory mechanisms independent of gene regulation may be responsible for the control of UCP3-mediated uncoupling activity.

Animals↗
PubMed2005

Uncoupling protein 3 protects aconitase against inactivation in isolated skeletal muscle mitochondria.

Mitochondrial uncoupling proteins only catalyse proton transport when they are activated. Activators include superoxide and reactive alkenals, suggesting new physiological functions for UCP2 and UCP3: their activation by superoxide when protonmotive force is high causes mild uncoupling, which lowers protonmotive force and attenuates superoxide generation by the electron transport chain. This feedback loop acts to prevent excessive mitochondrial superoxide production. Superoxide inactivates aconitase in the mitochondrial matrix, so aconitase activity provides a sensitive measure of the effects of UCPs on matrix superoxide. We find that inhibition of UCP3 in isolated skeletal muscle mitochondria by GDP decreases aconitase activity by 25% after 20 min incubation. The GDP effect is absent in skeletal muscle mitochondria from UCP3 knockout mice, showing that it is mediated by UCP3. Protection of aconitase by UCP3 in the absence of nucleotides does not require added fatty acids. The purine nucleoside diphosphates and triphosphates cause aconitase inactivation, but the monophosphates and CDP do not, consistent with the known nucleotide specificity of UCP3. The IC(50) for GDP is about 100 microM. These findings support the proposal that UCP3 attenuates endogenous radical production by the mitochondrial electron transport chain at high protonmotive force.

Aconitate Hydratase↗
PubMed2002

Skeletal muscle mitochondrial efficiency and uncoupling protein 3 in overeating rats with increased thermogenesis.

To establish whether changes in skeletal muscle mitochondrial efficiency contribute to increased energy expenditure and decreased metabolic efficiency of overeating rats with increased thermogenesis, we measured basal proton leak, fatty acid-induced uncoupling and uncoupling protein 3 (UCP3) content in subsarcolemmal and intermyofibrillar skeletal muscle mitochondria. Intermyofibrillar, but not subsarcolemmal, mitochondria from rats with increased thermogenesis exhibited a lower proton leak compared with controls. In both mitochondrial populations from rats with increased thermogenesis, fatty acid-induced uncoupling was increased significantly and a small recoupling effect of GDP was detected. In addition, intermyofibrillar and subsarcolemmal mitochondria from rats with increased thermogenesis showed higher UCP3 contents than controls. These results point out that metabolic efficiency in subsarcolemmal and intermyofibrillar mitochondria from rats with increased thermogenesis is differently regulated. In fact, in intermyofibrillar mitochondria both basal proton leak and fatty acid-induced uncoupling are altered, while in subsarcolemmal mitochondria only fatty acid-induced uncoupling increases. Both mitochondrial populations in skeletal muscle cells from rats with increased thermogenesis display an increased fatty acid-induced uncoupling and UCP3 content, which could contribute to avoiding obesity.

Animals↗
PubMed2006

The effects of uncoupling protein 3 haplotypes on obesity phenotypes and very low-energy diet-induced changes among overweight Korean female subjects.

Responses to energy restriction tend to vary within the population because of genetic differences. In this study, we have genotyped 6 uncoupling protein 3 (UCP-3) polymorphisms (-55C/T, Int2-143G/C, Tyr99Tyr, Int3-47G/A, Int4-498C/T, and Tyr210Tyr) among 214 overweight Korean female subjects recruited from an obesity clinic. Three major haplotypes, identified with frequencies in excess of 0.04, were constructed from 6 single nucleotide polymorphisms. Association studies were then undertaken, involving the measurement of anthropometric characteristics and body composition both before and after 1 month of a energy-restriction regimen. At baseline, haplotype 1 (ht1) [CGTACC] was associated with elevated anthropometric characteristics, including body weight, waist-hip ratio, and body mass index, as well as body components, including body fat mass and body fat-free mass. After the completion of the 1-month weight control program, which involved a very low-energy (2900 kJ/d) diet, we analyzed the outcomes according to the UCP-3 genetic polymorphisms. Among the 3 principal haplotypes, ht1 [CGTACC] was significantly associated with an increased reduction in body weight, in the codominant (P=.022), dominant (P=.016), and recessive (P=.041) models. Body mass index reduction was associated with the ht1 haplotype in a similar fashion. Among the body components, changes in body fat mass were significantly associated with ht1 [CGTACC] (P=.028), but changes in body fat-free mass were not significantly associated with the UCP-3 polymorphism.

Adult↗
PubMed2005

Effect of polymorphism of uncoupling protein 3 gene -55 (C>T) on the resting energy expenditure, total body fat and regional body fat in Chinese.

OBJECTIVE: To investigate the relationship of the C to T variant at the -55 site of the promoter region of uncoupling protein 3 gene (UCP3) with the resting energy expenditure and the parameters of body fat in Chinese population. METHODS: Three hundred Chinese (91 normal weight subjects, 209 overweight/obesity subjects) were genotyped for the UCP3 gene -55(C>T) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Resting energy expenditure (REE), fat mass (FM), fat free mass (FFM) and the parameters for regional adipose tissue distribution were measured. RESULTS: Genotype frequencies of UCP3 gene -55(C>T) were not associated with obesity and different types of obesity. The REE level in normal weight subjects with TT homozygotes was higher than that in those with CT heterozygotes and CC homozygotes (P=0.0200). Similar tendency was also observed in overweight/obesity subjects. The FM/FFM exhibited significant difference between the overweight/obesity subjects with a TT genotype and those with a CT or CC genotype (P=0.0096). CONCLUSION: The level of difference in REE caused by the polymorphism of promoter region of UCP3 -55(C>T) may play a role in energy metabolism in Chinese.

Adipose Tissue↗
PubMed2003

Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo.

Phosphocreatine (PCr) resynthesis rate following intense anoxic contraction can be used as a sensitive index of in vivo mitochondrial function. We examined the effect of a diet-induced increase in uncoupling protein 3 (UCP3) expression on postexercise PCr resynthesis in skeletal muscle. Nine healthy male volunteers undertook 20 one-legged maximal voluntary contractions with limb blood flow occluded to deplete muscle PCr stores. Exercise was performed following 7 days consumption of low-fat (LF) or high-fat (HF) diets. Immediately following exercise, blood flow was reinstated, and muscle was sampled after 20, 60, and 120 seconds of recovery. Mitochondrial coupling was assessed by determining the rate of PCr resynthesis during recovery. The HF diet increased UCP3 protein content by approximately 44% compared with the LF diet. However, this HF diet-induced increase in UCP3 expression was not associated with any changes in the rate of muscle PCr resynthesis during conditions of maximal flux through oxidative phosphorylation. Muscle acetylcarnitine, free-creatine, and lactate concentrations during recovery were unaffected by the HF diet. Taken together, our findings demonstrate that increasing muscle UCP3 expression does not diminish the rate of PCr resynthesis, allowing us to conclude that the primary role of UCP3 in humans is not uncoupling.

Adult↗
PubMed2003

Skeletal muscle mitochondrial oxidative capacity and uncoupling protein 3 are differently influenced by semistarvation and refeeding.

We investigated, in skeletal muscle mitochondria isolated from semistarved and refed rats, the relation between the protein expression of uncoupling protein 3 (UCP3) and mitochondrial oxidative capacity, assessed as state 4 and state 3 respiration rates in presence of substrates that are either non-lipids (glutamate, succinate) or lipids (palmitoyl CoA, palmitoylcarnitine). During semistarvation, when whole-body thermogenesis is diminished, state 3 respiration was lower than in fed controls by about 30% independently of substrate types, while state 4 respiration was lower by 20% only during succinate oxidation, but UCP3 was unaltered. After 5 days of refeeding, when thermogenesis is still diminished, neither state 4, state 3 nor UCP3 were lower than in controls. Refeeding on a high-fat diet, which exacerbates the suppression of thermogenesis, resulted in a two-fold elevation in UCP3 but no change in state 4 or state 3 respiration. These results during semistarvation and refeeding, in line with those previously reported for fasting, are not in support of the hypothesis that UCP3 is a mediator of adaptive thermogenesis pertaining to weight regulation, and underscore the need for caution in interpreting parallel changes in UCP3 and mitochondrial oxidative capacity as the reflection of mitochondrial uncoupling by UCP3.

Animal Feed↗
PubMed2004

Genetic variation in uncoupling protein 3 is associated with dietary intake and body composition in females.

The uncoupling proteins (UCPs) are a family of mitochondrial transport proteins that promote proton leakage across the inner mitochondrial membrane, uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) production and releasing energy as heat. Variation in these genes may disrupt biochemical pathways influencing thermogenesis, energy metabolism, and fuel substrate partitioning and oxidation, which may in turn predispose to obesity. We genotyped polymorphisms in UCP2 and UCP3 in a sample of nondiabetic participants (n = 722) of the San Luis Valley Diabetes Study (SLVDS) and found female-specific associations between UCP3 polymorphisms and measures of dietary intake and body composition. The UCP3-5 variant was statistically significantly associated with total caloric intake (P =.012), fat intake (P =.011), fat mass (P =.004), and lean mass (P =.013), with the C allele corresponding to higher dietary intake and lower fat mass and lean mass. The UCP3p-55 and the UCP3-3 polymorphisms, which were in high linkage disequilibrium (D' = 0.9776), showed similar patterns of association with total caloric intake (P =.031 and P =.042, respectively) and lean mass (P =.035 and P =.059, respectively), with the rare alleles corresponding to higher total intake and lean mass. No statistically significant associations were detected between the outcome variables and polymorphisms in UCP2. Two-way analysis of covariance (ANCOVA), used to evaluate the multi-locus effects and interactions between UCP3-5 and UCP3p-55, showed association with the main effect terms, but no evidence for statistically significant interaction between UCP3-5 and UCP3p-55 in regard to dietary intake. The UCP3-5 polymorphism was the only statistically significant genetic predictor of fat mass. The lean mass model showed no statistically significant association with either UCP3 variant. These results support a role for UCP3 in fuel substrate management and energy metabolism, which may influence body weight regulation.

Alleles↗
PubMed2001

Chronic docosahexaenoic acid intake enhances expression of the gene for uncoupling protein 3 and affects pleiotropic mRNA levels in skeletal muscle of aged C57BL/6NJcl mice.

Docosahexaenoic acid [DHA, 22:6(n-3)] prevents cardiovascular disease by decreasing obesity. It also prevents cancer and other geriatric diseases. We studied the chronic pleiotropic effects of DHA on transcription including that of mRNAs for uncoupling proteins (UCP). Male and female mice (9 mo old) were fed high (n-6) or high (n-3) fatty acid diets for 4 mo. Compared with controls fed high (n-6) fatty acid diets [high (n-6) group], the livers of male and female mice fed DHA [high (n-3) group] contained six- (P < 0.001) and fivefold (P < 0.001) more DHA, respectively. The high (n-3) group had less white adipose tissue [35.3% in males (P < 0.001) and 27.3% in females (P < 0.001)]. The high (n-3) group expressed more uncoupling protein 3 (UCP3) in the gastrocnemius, 108% higher (P < 0.001) and 104% higher (P < 0.001) in males and females, respectively, than those in the high (n-6) group. However, the prevention of many diseases by DHA is not explained by UCP3. Thus, the gene expression profiles of both high (n-3) and high (n-6) groups were analyzed in skeletal muscle using cDNA expression array. Of 588 genes surveyed in the array, the high (n-3) group showed 12 genes (2%) including those for glucose regulators (e.g., CD38) and tumor suppressors (e.g., CTCF) that were expressed 100-340% more than those of the high (n-6) group. Furthermore, 28 genes (4.8%), including growth factors (e.g., ErbB-2 receptor) and immune regulators (e.g., interleukin-1 beta precursor) were expressed 50-90% less in the high (n-3) group than in the high (n-6) group. These results explain in part the important pleiotropic effects of DHA, which are independent of obesity control by UCP3 suppression.

Aging↗
PubMed2003

Up-regulation of muscle uncoupling protein 3 gene expression in mice following high fat diet, dietary vitamin A supplementation and acute retinoic acid-treatment.

OBJECTIVE: To analyse the impact of vitamin A supplementation of both a normal fat (NF) diet and a high fat (HF) diet and of acute retinoic acid (RA)-treatment on the expression of uncoupling protein 3 (UCP3) in mice. DESIGN: C57BL/6J mice were fed for 18 weeks a NF or a HF diet (10 and 45 energy% as fat, respectively), both with the normal vitamin A content or an excess vitamin A (8 mg and 320 mg retinyl palmitate/kg diet, respectively). Body weight and energy intake were recorded periodically. UCP3 mRNA and UCP3 protein levels in skeletal muscle (soleus/gastrocnemius) were analysed, as well as UCP1, UCP2 and UCP3 mRNA levels in interscapular brown adipose tissue (BAT), and UCP2 mRNA, UCP2 protein and leptin mRNA levels in white adipose tissue (WAT) depots. The effect of acute RA-treatment (100 mg/kg/day, 4 days) on UCP3 mRNA levels in skeletal muscle and BAT of NMRI mice was also assessed. RESULTS: Vitamin A supplementation of a NF diet led to increased levels of UCP3 mRNA and UCP3 protein in muscle, UCP1 mRNA in BAT, and UCP2 mRNA in inguinal WAT, but had no impact on body weight or adiposity of B6 mice. HF diet promoted obesity and increased levels of UCP3 mRNA and UCP3 protein in skeletal muscle, and of the mRNAs for all three UCPs in BAT. Supplementing the HF diet with vitamin A had little effect on the final obesity reached and did not lead to further increases of muscle UCP3 mRNA nor BAT UCP1 mRNA over the levels achieved with the non-supplemented HF diet. Adipose leptin mRNA levels were down regulated after vitamin A supplementation, independently of the fat content of the diet. Up-regulation of muscle, but not BAT, UCP3 mRNA levels was also found after acute RA-treatment in NMRI mice. CONCLUSION: The results provide evidence of a stimulatory effect of retinoids on muscle UCP3 expression in vivo, and a differential retinoid-regulation of the UCP3 gene in muscle and BAT.

Adipose Tissue↗
PubMed2002

Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3.

Five markers of different kinds of oxidative damage to proteins [glutamic semialdehyde, aminoadipic semialdehyde, N (epsilon)-(carboxymethyl)lysine, N (epsilon)-(carboxyethyl)lysine and N (epsilon)-(malondialdehyde)lysine] and phospholipid fatty acyl composition were identified and measured in skeletal muscle mitochondria isolated from mice genetically engineered to underexpress or overexpress uncoupling protein 3 (UCP3). Mitochondria from UCP3-underexpressing mice had significantly higher levels of oxidative damage than wild-type controls, suggesting that UCP3 functions in vivo as part of the antioxidant defences of the cell, but mitochondria from UCP3-overexpressing mice had unaltered oxidative damage, suggesting that mild uncoupling in vivo beyond the normal basal uncoupling provides little protection against oxidative stress. Mitochondria from UCP3-underexpressing mice showed little change, but mitochondria from UCP3-overexpressing mice showed marked changes in mitochondrial phospholipid fatty acyl composition. These changes were very similar to those previously found to correlate with basal proton conductance in mitochondria from a range of species and treatments, suggesting that high protein expression, or some secondary result of uncoupling, may cause the observed correlation between basal proton conductance and phospholipid fatty acyl composition.

Animals↗
PubMed2002

Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter.

The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein-3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by approximately 14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up-regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.

Adult↗
PubMed2006

Expression of uncoupling protein 3 and GLUT4 gene in skeletal muscle of preterm newborns: possible control by AMP-activated protein kinase.

We seek to understand the mechanism for the delayed postnatal switch between glycolytic and oxidative metabolism in preterm newborns. Our previous study [Brauner et al. (Pediatr Res 53: 691-697, 2003)] suggested impaired postnatal recruitment of the gene for mitochondrial uncoupling protein 3 (UCP3) by nutritional lipids in skeletal muscle of neonates delivered before approximately 26 wk of gestation. UCP3 is linked to lipid oxidation and may be involved in the defective development of energy metabolism in skeletal muscles of very preterm newborns. In extension of our previous study, autopsy samples of musculus quadriceps femoris from 40 mostly preterm neonates and 5 fetuses were used for quantification of transcripts for UCP3, GLUT4, and their transcriptional regulator, AMP-activated protein kinase (AMPK). The new analysis confirmed the defect in the recruitment of the UCP3 gene expression by lipids in very preterm neonates. It also suggested involvement of AMPK in the control of expression of both metabolic genes, UCP3 and GLUT4, in the skeletal muscle of the newborns. Experiments on adult C57BL/6J mice confirmed the relationships between the transcripts and supported the involvement of AMPK in the control of UCP3 gene expression.

Adult↗
PubMed2000

Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin.

AIMS/HYPOTHESIS: Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (-55 c-->t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. METHODS: The -55 c-->t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. RESULTS: In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the -55 c-->t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039). CONCLUSION/INTERPRETATION: The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.

Adipose Tissue↗