Effect of speed endurance training and reduced training volume on running economy and single muscle fiber adaptations in trained runners.

The aim of the present study was to examine whether improved running economy with a period of speed endurance training and reduced training volume could be related to adaptations in specific muscle fibers. Twenty trained male (n = 14) and female (n = 6) runners (maximum oxygen consumption (VO2 -max): 56.4 ± 4.6 mL/min/kg) completed a 40-day intervention with 10 sessions of speed endurance training (5-10 × 30-sec maximal running) and a reduced (36%) volume of training. Before and after the intervention, a muscle biopsy was obtained at rest, and an incremental running test to exhaustion was performed. In addition, running at 60% vVO2 -max, and a 10-km run was performed in a normal and a muscle slow twitch (ST) glycogen-depleted condition. After compared to before the intervention, expression of mitochondrial uncoupling protein 3 (UCP3) was lower (P < 0.05) and dystrophin was higher (P < 0.05) in ST muscle fibers, and sarcoplasmic reticulum calcium ATPase 1 (SERCA1) was lower (P < 0.05) in fast twitch muscle fibers. Running economy at 60% vVO2 -max (11.6 ± 0.2 km/h) and at v10-km (13.7 ± 0.3 km/h) was ~2% better (P < 0.05) after the intervention in the normal condition, but unchanged in the ST glycogen-depleted condition. Ten kilometer performance was improved (P < 0.01) by 3.2% (43.7 ± 1.0 vs. 45.2 ± 1.2 min) and 3.9% (45.8 ± 1.2 vs. 47.7 ± 1.3 min) in the normal and the ST glycogen-depleted condition, respectively. VO2 -max was the same, but vVO2 -max was 2.0% higher (P < 0.05; 19.3 ± 0.3 vs. 18.9 ± 0.3 km/h) after than before the intervention. Thus, improved running economy with intense training may be related to changes in expression of proteins linked to energy consuming processes in primarily ST muscle fibers.

Mitochondrial efficiency and exercise economy following heat stress: a potential role of uncoupling protein 3.

Heat stress has been reported to reduce uncoupling proteins (UCP) expression, which in turn should improve mitochondrial efficiency. Such an improvement in efficiency may translate to the systemic level as greater exercise economy. However, neither the heat-induced improvement in mitochondrial efficiency (due to decrease in UCP), nor its potential to improve economy has been studied. Determine: (i) if heat stress in vitro lowers UCP3 thereby improving mitochondrial efficiency in C2C12 myocytes; (ii) whether heat acclimation (HA) in vivo improves exercise economy in trained individuals; and (iii) the potential improved economy during exercise at altitude. In vitro, myocytes were heat stressed for 24 h (40°C), followed by measurements of UCP3, mitochondrial uncoupling, and efficiency. In vivo, eight trained males completed: (i) pre-HA testing; (ii) 10 days of HA (40°C, 20% RH); and (iii) post-HA testing. Pre- and posttesting consisted of maximal exercise test and submaximal exercise at two intensities to assess exercise economy at 1600 m (Albuquerque, NM) and 4350 m. Heat-stressed myocytes displayed significantly reduced UCP3 mRNA expression and, mitochondrial uncoupling (77.1 ± 1.2%, P < 0.0001) and improved mitochondrial efficiency (62.9 ± 4.1%, P < 0.0001) compared to control. In humans, at both 1600 m and 4350 m, following HA, submaximal exercise economy did not change at low and moderate exercise intensities. Our findings indicate that while heat-induced reduction in UCP3 improves mitochondrial efficiency in vitro, this is not translated to in vivo improvement of exercise economy at 1600 m or 4350 m.

Capsiate supplementation reduces oxidative cost of contraction in exercising mouse skeletal muscle in vivo.

Chronic administration of capsiate is known to accelerate whole-body basal energy metabolism, but the consequences in exercising skeletal muscle remain very poorly documented. In order to clarify this issue, the effect of 2-week daily administration of either vehicle (control) or purified capsiate (at 10- or 100-mg/kg body weight) on skeletal muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in mice. Mechanical performance and energy metabolism were assessed strictly non-invasively in contracting gastrocnemius muscle using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Regardless of the dose, capsiate treatments markedly disturbed basal bioenergetics in vivo including intracellular pH alkalosis and decreased phosphocreatine content. Besides, capsiate administration did affect neither mitochondrial uncoupling protein-3 gene expression nor both basal and maximal oxygen consumption in isolated saponin-permeabilized fibers, but decreased by about twofold the Km of mitochondrial respiration for ADP. During a standardized in vivo fatiguing protocol (6-min of repeated maximal isometric contractions electrically induced at a frequency of 1.7 Hz), both capsiate treatments reduced oxidative cost of contraction by 30-40%, whereas force-generating capacity and fatigability were not changed. Moreover, the rate of phosphocreatine resynthesis during the post-electrostimulation recovery period remained unaffected by capsiate. Both capsiate treatments further promoted muscle mass gain, and the higher dose also reduced body weight gain and abdominal fat content. These findings demonstrate that, in addition to its anti-obesity effect, capsiate supplementation improves oxidative metabolism in exercising muscle, which strengthen this compound as a natural compound for improving health.

Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and ß-oxidation via an UCP3/AMPK-dependent pathway in skeletal muscle.

SCOPE: Ursolic acid (UA) is a triterpenoid compound with multifold biological functions. Our previous studies have reported that UA protects against high-fat diet-induced obesity and improves insulin resistance (IR). However, the potential mechanisms are still undefined. Free fatty acid (FFA) metabolism in skeletal muscle plays a central role in obesity and IR. Therefore, in this study, we investigated the effect and the potential mechanisms of UA on skeletal muscle FFA metabolism. METHODS AND RESULTS: In diet-induced obese rats, 0.5% UA supplementation for 6 weeks markedly reduced body weight, increased energy expenditure, decreased FFA level in serum and skeletal muscle and triglyceride content in skeletal muscle. In vitro, the data provided directly evidence that UA significantly increased fluorescently labeled FFA uptake and (3) H-labeled palmitic acid ß-oxidation. UA-activated AMP-activated protein kinase (AMPK) and downstream targets were involved in the increase of FFA catabolism. Moreover, upregulated uncoupling protein 3 (UCP3) by UA contributed to AMPK activation via elevating adenosine monophosphate/adenosine triphosphate ratio. CONCLUSION: UA increases FFA burning through enhancing skeletal muscle FFA uptake and ß-oxidation via an UCP3/AMPK-dependent pathway, which provides a novel perspective on the biological function of UA against obesity and IR.

R-α lipoic acid γ-cyclodextrin complex increases energy expenditure: a 4-month feeding study in mice.

OBJECTIVE: A high-fat diet (HFD) affects energy expenditure in laboratory rodents. R-α lipoic acid cyclodextrin (RALA-CD) complex is a stable form of lipoic acid (LA) and may improve energy expenditure. The aim of this study was to determine the effect of RALA-CD on energy expenditure and underlying molecular targets in female laboratory mice. METHODS: Female C57BL/6J mice were fed a HFD containing 0.1% LA for about 16 wk. The effects on energy expenditure, gene and protein expression were assessed using indirect calorimetry, real-time reverse transcriptase polymerase chain reaction, and Western blot, respectively. RESULTS: Supplementing mice with RALA-CD resulted in a significant increase in energy expenditure. However, both RALA per se (without γ-cyclodextrin) and S-α lipoic acid cyclodextrin did not significantly alter energy expenditure. Furthermore RALA-CD changed expression of genes encoding proteins centrally involved in energy metabolism. Transcriptional key regulators sirtuin 3 and peroxisome proliferator-activated receptor-γ, coactivator 1 alpha, as well as thyroid related enzyme type 2 iodothyronine deiodinase were up-regulated in brown adipose tissue (BAT) of RALA-CD-fed mice. Importantly, mRNA and/or protein expression of downstream effectors uncoupling protein (Ucp) 1 and 3 also were elevated in BAT from RALA-CD-supplemented mice. CONCLUSION: Overall, present data suggest that RALA-CD is a regulator of energy expenditure in laboratory mice.

The role of uncoupling protein 2 and 3 genes polymorphism and energy expenditure in obese Indonesian children.

AIM: Uncoupling protein (UCP) genes, which may contribute to energy metabolism in mitochondria, may be involved in the pathogenesis of obesity. We analyzed the differences in energy expenditure between single nucleotide polymorphisms (SNPs) UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V among Indonesian children. METHODS: The study included 76 schoolchildren (36 obese and 40 healthy; mean age, 12.8 years) in Semarang, Indonesia. Body composition was measured by bioelectrical impedance analysis; resting energy expenditure (REE) by indirect calorimetry; physical activity by uniaxial accelerometer; and total energy expenditure (TEE) by the equations extrapolated from REE and physical activity. UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V were examined by restriction length fragment polymorphism analysis. RESULTS: The TEE of the subjects with the T/T genotype at UCP3-55C/T after adjusting for fat-free mass (63.2±7.2 kcal/kg/day) and T/T at UCP2 A55V (62.8±5.6 kcal/kg/day) was lower than that of the subjects with the C/C and C/T genotypes (p<0.05). The REE of the subjects with these T/T genotypes tended to be lower than that of the subjects with C/C and C/T (p≥0.05). No significant differences in REE or TEE were found between the UCP3 Y210Y genotypes. CONCLUSIONS: The subjects with the T/T genotypes of UCP3-55C/T or UCP2 A55V had lower TEE than those with other genotypes.

Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity.

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake.

[UCP2 and UCP3 gene expression, heart function and oxygen cost of myocardial work changes during aging and ischemia-reperfusion].

To examine the effects of ischemia/reperfusion on UCPs genes expression, heart function and oxygen cost of myocardial work, hearts of adult (6 mo) and old (24 mo) rats were perfused by Langendorf preparation and subjected to 20 min ischemia followed by 40 min reperfusion. Mitochondrial permeability transition due to ischemic stimuli was evaluated by release of mitochondrial factor (lambda 250 nm) which was previously shown as a marker of MPTP opening. Expression of UCPs was detected by reverse transcriptional polymerase chain reaction. Mitochondrial membrane potential (deltaphi(m)) and oxygen consumption in isolated heart mitochondria of adult and old rats were measured. It was shown that impaired function of aging rat hearts was accompanied with an increased oxygen cost of myocardial work and lower mitochondrial membrane potential compared with adult rats. Reperfusion disturbances of cardiodynamic, contractile activity of myocardium and noneffective oxygen utilization in early period of reperfusion were less intensive in aged hearts than in adult ones. Therefore, the levels of mRNA of UCP2 in aging hearts were higher and mRNA levels of UCP3 were tended to increase. At the same time ischemia/reperfusion increased the expression of UCP2 and UCP3 in adult myocardium: mRNA levels of UCPs were significantly higher that those in control, whereas there was no such effect in aging hearts. It is concluded that uncoupling proteins are implicated in the age-depended heart dysfunction and development of the pathological mechanisms during ischemia-reperfusion.

Several obesity- and nutrient-related gene polymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB study.

BACKGROUND: Part of the heterogeneity of the obesity phenotype may originate from genetic differences between obese individuals that may influence energy expenditure (EE). OBJECTIVE: To examine if common single-nucleotide polymorphisms (SNPs) in genes related to obesity-associated phenotypes are associated with postabsorptive resting energy expenditure (REE) and postprandial REE in obese individuals. DESIGN AND METHODS: Postabsorptive REE and 3-h postprandial REE (liquid test meal containing 95% fat, energy content 50% of estimated REE) were measured in 743 obese individuals from eight clinical centres in seven European countries. The analysis assessed the association of genotypes of 44 SNPs in 28 obesity-related candidate genes with postabsorptive REE and postprandial REE taking into consideration the influence of body composition, habitual physical activity, insulin sensitivity, circulating thermogenic hormones and metabolites. RESULTS: After adjustment for fat-free mass (FFM), age, sex and research centre, SNPs in CART, GAD2, PCSK1, PPARG3, HSD11B1 and LIPC were significantly associated with postabsorptive REE. SNPs in GAD2, HSD11B1 and LIPC remained significantly associated with postabsorptive REE after further adjustment for fat mass (FM). SNPs in CART, PPARG2 and IGF2 were significantly associated with postprandial REE after similar adjustments. These associations with postprandial REE remained significant after further adjustment for FM. FTO, UCP2 and UCP3 variants were not associated with postabsorptive or postprandial REE. CONCLUSIONS: Several gene polymorphisms associated with obesity-related phenotypes but not FTO and UCP variants may be responsible for some of the inter-individual variability in postabsorptive REE and fat-induced thermogenesis unaccounted for by FFM, FM, age and sex. The association between FTO and obesity that has been reported earlier may not be mediated directly through modulation of EE in obese individuals.

Four weeks of speed endurance training reduces energy expenditure during exercise and maintains muscle oxidative capacity despite a reduction in training volume.

We studied the effect of an alteration from regular endurance to speed endurance training on muscle oxidative capacity, capillarization, as well as energy expenditure during submaximal exercise and its relationship to mitochondrial uncoupling protein 3 (UCP3) in humans. Seventeen endurance-trained runners were assigned to either a speed endurance training (SET; n = 9) or a control (Con; n = 8) group. For a 4-wk intervention (IT) period, SET replaced the ordinary training ( approximately 45 km/wk) with frequent high-intensity sessions each consisting of 8-12 30-s sprint runs separated by 3 min of rest (5.7 +/- 0.1 km/wk) with additional 9.9 +/- 0.3 km/wk at low running speed, whereas Con continued the endurance training. After the IT period, oxygen uptake was 6.6, 7.6, 5.7, and 6.4% lower (P < 0.05) at running speeds of 11, 13, 14.5, and 16 km/h, respectively, in SET, whereas remained the same in Con. No changes in blood lactate during submaximal running were observed. After the IT period, the protein expression of skeletal muscle UCP3 tended to be higher in SET (34 +/- 6 vs. 47 +/- 7 arbitrary units; P = 0.06). Activity of muscle citrate synthase and 3-hydroxyacyl-CoA dehydrogenase, as well as maximal oxygen uptake and 10-km performance time, remained unaltered in both groups. In SET, the capillary-to-fiber ratio was the same before and after the IT period. The present study showed that speed endurance training reduces energy expenditure during submaximal exercise, which is not mediated by lowered mitochondrial UCP3 expression. Furthermore, speed endurance training can maintain muscle oxidative capacity, capillarization, and endurance performance in already trained individuals despite significant reduction in the amount of training.

A high-mobility, low-cost phenotype defines human effector-memory CD8+ T cells.

T cells move randomly ("random-walk"), a characteristic thought to be integral to their function. Using migration assays and time-lapse microscopy, we found that CD8+ T cells lacking the lymph node homing receptors CCR7 and CD62L migrate more efficiently in transwell assays, and that these same cells are characterized by a high frequency of cells exhibiting random crawling activity under culture conditions mimicking the interstitial/extravascular milieu, but not when examined on endothelial cells. To assess the energy efficiency of cells crawling at a high frequency, we measured mRNA expression of genes key to mitochondrial energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1beta [PGC-1beta], estrogen-related receptor alpha [ERRalpha], cytochrome C, ATP synthase, and the uncoupling proteins [UCPs] UCP-2 and -3), quantified ATP contents, and performed calorimetric analyses. Together these assays indicated a high energy efficiency of the high crawling frequency CD8+ T-cell population, and identified differentially regulated heat production among nonlymphoid versus lymphoid homing CD8+ T cells.

Short-term, increasing dietary protein and fat moderately affect energy expenditure, substrate oxidation and uncoupling protein gene expression in rats.

Macronutrient composition of diets can influence body-weight development and energy balance. We studied the short-term effects of high-protein (HP) and/or high-fat (HF) diets on energy expenditure (EE) and uncoupling protein (UCP1-3) gene expression. Adult male rats were fed ad libitum with diets containing different protein-fat ratios: adequate protein-normal fat (AP-NF): 20% casein, 5% fat; adequate protein-high fat (AP-HF): 20% casein, 17% fat; high protein-normal fat (HP-NF): 60% casein, 5% fat; high protein-high fat (HP-HF): 60% casein, 17% fat. Wheat starch was used for adjustment of energy content. After 4 days, overnight EE and oxygen consumption, as measured by indirect calorimetry, were higher and body-weight gain was lower in rats fed with HP diets as compared with rats fed diets with adequate protein content (P<.05). Exchanging carbohydrates by protein increased fat oxidation in HF diet fed groups. The UCP1 mRNA expression in brown adipose tissue was not significantly different in HP diet fed groups as compared with AP diet fed groups. Expression of different homologues of UCPs positively correlated with nighttime oxygen consumption and EE. Moreover, dietary protein and fat distinctly influenced liver UCP2 and skeletal muscle UCP3 mRNA expressions. These findings demonstrated that a 4-day ad libitum high dietary protein exposure influences energy balance in rats. A function of UCPs in energy balance and dissipating food energy was suggested. Future experiments are focused on the regulation of UCP gene expression by dietary protein, which could be important for body-weight management.

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.

Cost of transport is increased after cold exposure in Monodelphis domestica: training for inefficiency.

Monodelphis domestica (Didelphidae: Marsupialia) lacks brown adipose tissue and thus relies on skeletal muscle as its primary thermogenic organ. Following cold exposure, the aerobic capacity of skeletal muscle in these animals is greatly increased. We investigated the effects of this plastic response to thermogenesis on locomotion and muscle mechanics. In cold-exposed animals, cost of transport was 15% higher than in controls but was unaffected by exercise training. Twitch kinetics in isolated semitendinosus muscles of cold-exposed animals were characteristic of slow-oxidative fiber types. Both time-to-peak tension and half-relaxation time were longer and maximal shortening velocity was slower following cold exposure compared to either thermoneutral controls or exercise-trained animals. Further, muscles from the cold-exposed animals had greater fatigue resistance than either control or exercise-trained animals, indicating greater oxidative capacity. Finally, we identified an uncoupling protein 3 homologue, whose gene expression was upregulated in skeletal muscle of cold-exposed Monodelphis domestica. Cold exposure provided a potent stimulus for muscle plasticity, driving a fast-to-slow transition more effectively than exercise training. However, linked to the dramatic shift in muscle properties is an equally dramatic increase in whole animal muscle energetics during locomotion, suggesting an uncoupled state, or 'training for inefficiency'.

c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action.

Casitas b-lineage lymphoma (c-Cbl) is an E3 ubiquitin ligase that has an important role in regulating the degradation of cell surface receptors. In the present study we have examined the role of c-Cbl in whole-body energy homeostasis. c-Cbl-/- mice exhibited a profound increase in whole-body energy expenditure as determined by increased core temperature and whole-body oxygen consumption. As a consequence, these mice displayed a decrease in adiposity, primarily due to a reduction in cell size despite an increase in food intake. These changes were accompanied by a significant increase in activity (2- to 3-fold). In addition, c-Cbl-/- mice displayed a marked improvement in whole-body insulin action, primarily due to changes in muscle metabolism. We observed increased protein levels of the insulin receptor (4-fold) and uncoupling protein-3 (2-fold) in skeletal muscle and a significant increase in the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase. These findings suggest that c-Cbl plays an integral role in whole-body fuel homeostasis by regulating whole-body energy expenditure and insulin action.

Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice.

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(-/-) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 +/- 2.4 m whereas KO mice moved 30.1 +/- 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT -68%, WAT -29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice.

[UCP-3: regulation of genic expression on skeletal muscle and possible role on body weight control]. / UCP-3: regulação da expressão gênica no músculo esquelético e possível relação com o controle do peso corporal.

Uncoupling proteins constitute a subgroup of mitochondrial carrier proteins that are located in the inner mitochondrial membrane. By dissipating proton gradients, they act to uncouple respiration from oxidative phosphorylation and convert fuel to heat. Four homologous UCP isoforms have been identified. UCP-1, the first UCP to be described, is found exclusively in brown adipose tissue, UCP-2 in several tissues, UCP-3 in human skeletal muscle and rat brown adipose tissue and skeletal muscle, whereas UCP-4 is expressed in the brain. Expression of UCP-3 in the skeletal muscle and the brown adipose tissue may place these tissues as important mediators for adaptative thermogenesis. However, the role of UCP-3 in energy expenditure and as a cause of obesity has been controversial. There are evidences that UCP-3 can be regulated by energy substrates as fatty acids and glucose, by entering the muscle and stimulating UCP-3 to increase energy expenditure. Our aim in this review was to describe and discuss the available information on UCP-3 regulation and its possible relation with body weight control.

Effect of beta1- and beta2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans.

In humans, beta-adrenergic stimulation increases energy and fat metabolism. In the case of beta1-adrenergic stimulation, it is fueled by an increased lipolysis. We examined the effect of beta2-adrenergic stimulation, with and without a blocker of lipolysis, on thermogenesis and substrate oxidation. Furthermore, the effect of beta1-and beta2-adrenergic stimulation on uncoupling protein 3 (UCP3) mRNA expression was studied. Nine lean males received a 3-h infusion of dobutamine (DOB, beta1) or salbutamol (SAL, beta2). Also, we combined SAL with acipimox to block lipolysis (SAL+ACI). Energy and substrate metabolism were measured continuously, blood was sampled every 30 min, and muscle biopsies were taken before and after infusion. Energy expenditure significantly increased approximately 13% in all conditions. Fat oxidation increased 47 +/- 7% in the DOB group and 19 +/- 7% in the SAL group but remained unchanged in the SAL+ACI condition. Glucose oxidation decreased 40 +/- 9% upon DOB, remained unchanged during SAL, and increased 27 +/- 11% upon SAL+ACI. Plasma free fatty acid (FFA) levels were increased by SAL (57 +/- 11%) and DOB (47 +/- 16%), whereas SAL+ACI caused about fourfold lower FFA levels compared with basal levels. No change in UCP3 was found after DOB or SAL, whereas SAL+ACI downregulated skeletal muscle UCP3 mRNA levels 38 +/- 13%. In conclusion, beta2-adrenergic stimulation directly increased energy expenditure independently of plasma FFA levels. Furthermore, this is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma FFA concentrations in humans, despite an increase in energy expenditure upon beta2-adrenergic stimulation.

Altered gene expressions involved in energy expenditure in 5-HT(2C) receptor mutant mice.

Mice with a targeted null mutation of the serotonin 5-HT(2C) receptor gene exhibit hyperphagia that leads to a late-onset obesity. Here we show that oxygen consumption was decreased in fed and fasted obese mutants. No phenotypic differences were observed in uncoupling protein-1 (UCP-1) mRNA levels in brown adipose tissues and UCP-3 mRNA in skeletal muscle. UCP-2 mRNA levels were significantly increased in white adipose tissue (4-fold) and skeletal muscle (47%) in older obese mutant mice, whereas UCP-2 mRNA in liver are significantly increased in both young lean (54% increase) and older obese (52% increase) mutant mice. In contrast, 5-HT(2C) receptor mutants displayed age-dependent decreases in beta 3-adrenergic receptor (beta 3-AR) mRNA levels in white adipose tissue, however, no such changes were observed in brown adipose tissue. These results indicate that a mutation of 5-HT(2C) receptor gene leads to a secondary decrease in beta 3-AR gene expression that is related to enhanced adiposity.