Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in <i>Ucp3(−/−)</i> and wild-type mice

Bézaire, Véronic; Hofmann, Wolfgang; Kramer, J. K. G.; Kozak, Leslie P.; Harper, Mary‐Ellen

doi:10.1152/ajpendo.2001.281.5.e975

Cited by 78 publications

(83 citation statements)

References 37 publications

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“…A role for UCP3 in FA metabolism has been suggested, where UCP3 expedites rates of FA oxidation by acting as a protein that facilitates mitochondrial FA anion efflux (24, 45,46). Accordingly, a lack of UCP3 would eventually lead to accumulation of FA anions inside the matrix, and to disturbances in FA oxidation, which is consistent with reported abnormalities in fat oxidation in UCP3 knockout mice (2). The role of UCP3 in the regulation of mitochondrial state 4 respiration has also been the subject of considerable debate (7,9,34,38).…”

Section: Discussionsupporting

confidence: 81%

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic

Adhihetty²,

Hood³

2004

Journal of Applied Physiology

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Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis. J Appl Physiol 97: 976 -983, 2004. First published May 14, 2004 10.1152/japplphysiol.00336.2004In an effort to better characterize uncoupling protein-3 (UCP3) function in skeletal muscle, we assessed basal UCP3 protein content in rat intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial subfractions in conjunction with measurements of state 4 respiration. UCP3 content was 1.3-fold (P Ͻ 0.05) greater in IMF compared with SS mitochondria. State 4 respiration was 2.6-fold greater (P Ͻ 0.05) in the IMF subfraction than in SS mitochondria. GDP attenuated state 4 respiration by ϳ40% (P Ͻ 0.05) in both subfractions. The UCP3 activator oleic acid (OA) significantly increased state 4 respiration in IMF mitochondria only. We used chronic electrical stimulation (3 h/day for 7 days) to investigate the relationship between changes in UCP3 protein expression and alterations in state 4 respiration during contractile activity-induced mitochondrial biogenesis. UCP3 content was increased by 1.9-and 2.3-fold in IMF and SS mitochondria, respectively, which exceeded the concurrent 40% (P Ͻ 0.05) increase in cytochrome-c oxidase activity. Chronic contractile activity increased state 4 respiration by 1.4-fold (P Ͻ 0.05) in IMF mitochondria, but no effect was observed in the SS subfraction. The uncoupling function of UCP3 accounted for 50 -57% of the OA-induced increase in state 4 respiration in IMF mitochondria, which was independent of the induced twofold difference in UCP3 content due to chronic contractile activity. Thus modifications in UCP3 function are more important than changes in UCP3 expression in modifying state 4 respiration. This effect is evident in IMF but not SS mitochondria. We conclude that UCP3 at physiological concentrations accounts for a significant portion of state 4 respiration in both IMF and SS mitochondria, with the contribution being greater in the IMF subfraction. In addition, the contradiction between human and rat training studies with respect to UCP3 protein expression may partly be explained by the greater than twofold difference in mitochondrial UCP3 content between rat and human skeletal muscle. skeletal muscle; exercise; mitochondria; uncoupling protein-3

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Section: Discussionsupporting

confidence: 81%

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic

Adhihetty²,

Hood³

2004

Journal of Applied Physiology

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“…Studies of Ucp3 knockout mice have revealed reduced proton conductance and increased respiratory control ratio in skeletal muscle mitochondria [6,7]. However, these results have been challenged [32,33]. Increased efficiency of cellular ATP production has been reported in Ucp3 knockout mice, suggesting an uncoupling by UCP3 in skeletal muscle in vivo [34].…”

Section: Discussionmentioning

confidence: 99%

Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles

et al. 2007

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Aims/hypothesis Uncoupling protein (UCP) 3 is a mitochondrial inner membrane protein expressed predominantly in glycolytic skeletal muscles. Its role in vivo remains poorly understood. The aim of the present work was to produce a mouse model with moderate overproduction and proper fibre-type distribution of UCP3. Methods Transgenic mice were created with a 16 kb region encompassing the human UCP3 gene. Mitochondrial uncoupling was investigated on permeabilised muscle fibres. Changes in body weight, adiposity and glucose or insulin tolerance were assessed in mice fed chow and highfat diets. Indirect calorimetry was used to determine wholebody energy expenditure and substrate utilisation.Results Transgenic mice showed a twofold increase in UCP3 protein levels specifically in glycolytic muscles. Mitochondrial respiration revealed an increase of uncoupling in glycolytic but not in oxidative muscles. Transgenic mice gained less weight than wild-type littermates due to lower adipose tissue accretion when fed a high-fat diet. Animals showed a sexual dimorphism in metabolic responses. Female transgenic mice were more glucose-sensitive than wild-type animals, while male transgenic mice with high body weights had impaired glucose and insulin tolerance. Measurements of RQs in mice fed chow and high-fat diets suggested an impairment of metabolic flexibility in transgenic male mice. Conclusions/interpretation Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat dietinduced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation.

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“…Although there were significant increases in muscle UCP3 expression, there were no changes in mitochondrial proton leak. Bé zaire et al (45) conducted a similar study in wild-type mice and UCP3 knockout mice. Fasting caused a fourfold increase in UCP3 and a twofold increase in UCP2 in muscle of wild-type mice; however, similar to the findings of Cadenas et al, there were no changes in mitochondrial proton leak reactions.…”

Section: Discussionmentioning

confidence: 99%

“…It is also important that Bé zaire et al (45) document impaired fatty acid oxidation in UCP3 knockout mice compared with wild-type controls, as determined by indirect calorimetry. Regardless of mechanistic details, our findings are consistent with an important role for mitochondrial proton leak and UCP3 in regulating the efficiency of energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Decreased Mitochondrial Proton Leak and Reduced Expression of Uncoupling Protein 3 in Skeletal Muscle of Obese Diet-Resistant Women

et al. 2002

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Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and dietresponsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P ‫؍‬ 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5 flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects. Diabetes 51: 2459 -2466, 2002 A t the Weight Management Program at the University of Ottawa, we have documented a 10-fold variation in the rate of weight loss in 353 highly compliant women on a standard exercise program and standard 900-kcal meal replacement protocol. These women were ranked according to percent body weight loss, and highest and lowest quintiles were defined as diet responsive and diet resistant, respectively. Regression analyses demonstrated that the known variables regulating energy requirements, including initial weight, age, and plasma free triiodothyronine (T3) concentrations, accounted for only half of this variability (1), leading us to search for novel molecular determinants of weight loss success.Variable responses to overfeeding have been reported. Rodent studies have demonstrated that genetic factors not only regulate weight gain in response to high-fat highcalorie diets but also determine the susceptibility to obesity when energy intake is controlled (2). In response to the ingestion of hypercaloric diets, the majority of subjects gain less weight than anticipated, and a process of adaptive thermogenesis appears to play a role in the defense against obesity (3). Several studies have demonstrated marked interindividual variability in the susceptibility to weight gain in response to overfeeding (4), and identical twins show marked similarity in this regard, suggesting an important genetic cont...

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Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(−/−) and wild-type mice

Cited by 78 publications

References 37 publications

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles

Decreased Mitochondrial Proton Leak and Reduced Expression of Uncoupling Protein 3 in Skeletal Muscle of Obese Diet-Resistant Women

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