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.

Claire Tiraby 1 Geneviève Tavernier 1, * Frédéric Capel 1 Aline Mairal 1 François Crampes 1 Jacques Rami 1 C. Pujol 1 J. A. Boutin 2 Dominique Langin 1, 3
* Auteur correspondant
1 I2MR - Institut de médecine moléculaire de Rangueil
2 Division de Pharmacologie Moléculaire et Cellulaire
3 Laboratoire de Biochimie [Purpan]
Abstract : 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 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/INTERPRETATION: 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.
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Diabetologia, Springer Verlag, 2007, 50 (10), pp.2190-9. 〈10.1007/s00125-007-0765-2〉
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Soumis le : jeudi 13 août 2009 - 10:34:28
Dernière modification le : jeudi 13 septembre 2018 - 10:26:05

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Claire Tiraby, Geneviève Tavernier, Frédéric Capel, Aline Mairal, François Crampes, et al.. 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.. Diabetologia, Springer Verlag, 2007, 50 (10), pp.2190-9. 〈10.1007/s00125-007-0765-2〉. 〈inserm-00409812〉

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