Triiodothyronine‐mediated upregulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes

Barbe, P; Larrouy, Dominique; Boulanger, Catherine; Chevillotte, Emmanuel; Viguerie, Nathalie; Thalamas, Claire; Trastoy, Manel Oliva; Roques, M; Vidal, Hubert; Langin, Dominique

doi:10.1096/fj.00-0502fje

Cited by 103 publications

(69 citation statements)

References 52 publications

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“…type IIB≥type IIA/IIX>type I, in transgenic mice was similar to the endogenous profile described in human skeletal muscle [4]. Moreover, regulation by thyroid hormone and fasting was observed as shown earlier in humans [13,17]. Therefore, all regulatory sequences crucial for tissue and fibre type distribution, as well as for hormonal and nutritional regulation were present in the 16 kb transgene.…”

Section: Discussionsupporting

confidence: 81%

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Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

et al. 2009

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Aims/hypothesis Uncoupling protein (UCP) 3 is an inner mitochondrial membrane transporter mainly produced in skeletal muscle in humans. UCP3 plays a role in fatty acid metabolism and energy homeostasis and modulates insulin sensitivity. In humans, UCP3 content is higher in fasttwitch glycolytic muscle than in slow-twitch oxidative muscle and is dysregulated in type 2 diabetes. Here, we studied the molecular mechanisms determining human UCP3 levels in skeletal muscle and their regulation by fasting in transgenic mice. Methods We produced a series of transgenic lines with constructs bearing different putative regulatory regions of the human UCP3 gene, including promoter and intron sequences. UCP3 mRNA and reporter gene expression and activity were measured in different skeletal muscles and tissues. Results The profile of expression and the response to fasting and thyroid hormone of human UCP3 mRNA in transgenic mice with 16 kb of the human UCP3 gene were similar to that of the endogenous human gene. Various parts of the UCP3 promoter did not confer expression in transgenic lines. Inclusion of intron 1 resulted in an expression profile in skeletal muscle that was identical to that of human UCP3 mRNA. Further dissection of intron 1 revealed that distinct regions were involved in skeletal muscle expression, distribution among fibre types and response to fasting. Conclusions/interpretation The control of human UCP3 transcription in skeletal muscle is not solely conferred by the promoter, but depends on several cis-acting elements in intron 1, suggesting a complex interplay between the promoter and intronic sequences.

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Section: Discussionsupporting

confidence: 81%

“…Fatty acids are potential mediators of this effect, which may at least in part depend on the activation of peroxisome proliferator-activated receptor (PPAR)α in skeletal muscle [15]. Thyroid hormones are also strong inducers of UCP3 expression in humans and in mice [14,16,17].…”

Section: Introductionmentioning

confidence: 99%

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

et al. 2009

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“…The overexpression of UCP3 is much lower than that of most of the previous models both in terms of mRNA (66-and 18-fold induction) and protein (25-and 15-fold induction) [27,28]. Moreover, the range of expression in h-UCP3 mice is compatible with the inductions observed in vivo in humans during fasting and thyroid hormone or etomoxir treatments [19][20][21]. A recent study reported data with a twofold overexpression of UCP3 in hindlimb muscle of C57Bl/6 mice [29,30].…”

Section: Discussionmentioning

confidence: 72%

“…This strategy ensured moderate UCP3 overproduction specifically targeting type II skeletal muscles. Therefore, the UCP3 distribution seen in human tissues and the physiological range of variations observed in clinical studies were respected [5,[19][20][21]. Mitochondrial uncoupling was investigated on permeabilised muscle fibres.…”

Section: Introductionmentioning

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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“…30 Thyroid hormone treatment, known to increase metabolic rate, induces UCP3 mRNA expression in humans. 31 Further evidence for a role of UCP3 in energy metabolism comes from transgenic mice models. Mice overexpressing UCP3 in skeletal muscle have been generated and these mice are lean despite an increased energy intake compared to controls.…”

Section: Discussionmentioning

confidence: 99%

The effect of mild cold exposure on UCP3 mRNA expression and UCP3 protein content in humans

Schrauwen

Kornips

et al. 2002

Int J Obes

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OBJECTIVE:In rodents, adaptive thermogenesis in response to cold exposure and high-fat feeding is accomplished by the activation of the brown adipose tissue specific mitochondrial uncoupling protein, UCP1. The recently discovered human uncoupling protein 3 is a possible candidate for adaptive thermogenesis in humans. In the present study we examined the effect of mild cold exposure on the mRNA and protein expression of UCP3. SUBJECTS: Ten healthy male volunteers (age 24.4 AE 1.6 y; height 1.83 AE 0.02 m; weight 77.3 AE 3.0 kg; percentage body fat 19 AE 2) DESIGN: Subjects stayed twice in the respiration chamber for 60 h (20.00 -8.00 h); once at 22 C (72 F), and once at 16 C (61 F). After leaving the respiration chamber, muscle biopsies were taken and RT-competitive-PCR and Western blotting was used to measure UCP3 mRNA and protein expression respectively. RESULTS: Twenty-four-hour energy expenditure was significantly increased at 16 C compared to 22 C (P < 0.05). At 16 C, UCP3T (4.6 AE 1.0 vs 7.7 AE 1.5 amol=mg RNA, P ¼ 0.07), UCP3L (2.0 AE 0.5 vs 3.5 AE 0.9 amol=mg RNA, P ¼ 0.1) and UCP3S (2.6 AE 0.6 vs 4.2 AE 0.7 amol=mg RNA, P ¼ 0.07) mRNA expression tended to be lower compared with at 22 C, whereas UCP3 protein content was, on average, not different. However, the individual differences in UCP3 protein content (16 -22 C) correlated positively with the differences in 24 h energy expenditure (r ¼ 0.86, P < 0.05). CONCLUSION: The present study suggests that UCP3 protein content is related to energy metabolism in humans and might help in the metabolic adaptation to cold exposure. However, the down-regulation of UCP3 mRNA with mild cold exposure suggests that prolonged cold exposure will lead to lower UCP3 protein content. What the function of such down-regulation of UCP3 could be is presently unknown.

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Triiodothyronine‐mediated upregulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes

Cited by 103 publications

References 52 publications

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

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

The effect of mild cold exposure on UCP3 mRNA expression and UCP3 protein content in humans

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