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.
OBJECTIVE
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 high-fat diets. Indirect calorimetry was used to determine whole-body 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
Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat diet-induced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation.
Inserm U858, Laboratoire de recherches sur les obésités, Institut de Médecine Moléculaire de Rangueil, Equipe 4, 1 avenue Jean Poulhès, P.O. Box 84225, 31432, Toulouse Cedex 4, France.
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Tiraby
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Tavernier
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Capel
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Mairal
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Crampes
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Rami
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Pujol
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Boutin
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Langin
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004041:Dietary Fats; D005260:Female; D005786:Gene Expression Regulation; D006019:Glycolysis; D007333:Insulin Resistance; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012727:Sex Characteristics; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D004041:Dietary Fats; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3