Reduction of diet-induced obesity in transgenic mice overexpressing uncoupling protein 3 in skeletal muscle

Son, Cheol; Hosoda, Kiminori; Ishihara, Kengo; Bevilacqua, Lisa; Masuzaki, Hiroaki; Fushiki, Tohru; Harper, Mary‐Ellen; Nakao, Kazuwa

doi:10.1007/s00125-003-1272-8

Cited by 57 publications

(51 citation statements)

References 31 publications

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“…In HFD-Leu mice, increased UCP3-mediated mitochondrial uncoupling of oxidative phosphorylation in thermogenic tissues likely accounts for the increased resting energy expenditure with reduced fuel efficiency. Our result is consistent with the reports that increased UCP3 expression reduces HFD-induced weight gain in transgenic mice (35) and is associated with the obesity-resistant phenotype in rats (34). Additionally, increases in muscle UCP3 expression level are generally seen in obese rats and humans (36,37), and weight loss results in decreases in muscle UCP3 expression in humans (37,38).…”

Section: Discussionsupporting

confidence: 92%

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

et al. 2007

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Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (P < 0.05) and a 25% decrease in adiposity (P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% (P < 0.001) and 53% (P < 0.001), respectively, in leucine supplemented HFDfed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms.

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Section: Discussionsupporting

confidence: 92%

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

et al. 2007

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“…The rank order of expression, type IIB≥type IIA>type I, is similar to the endogenous profile described in human skeletal muscles [5]. Previous transgenic models relied on heterologous promoters with activities in different fibre types and possibly in heart [27,28]. Therefore, the increased expression of UCP3 specifically within glycolytic skeletal muscles is a major strength of the model.…”

Section: Discussionmentioning

confidence: 53%

“…In mitochondria from the gastrocnemius muscle, UCP3 protein levels are doubled in h-UCP3 mice compared with WT animals. 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].…”

Section: Discussionmentioning

confidence: 70%

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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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“…Other UCPs may answer to nucleotides and fatty acids in a similar way to UCP1 but the physiological context is unique and thus their physiological regulation is likely to be diff erent 9 . The importance of UCPs is clear from the list of their involvement in various processes: prevention of reactive oxygen species (ROS) formation 10 , prevention of atherosclerosis 11 , one of the etiologies of type-2 diabetes 12 , participation in infl ammation 10 , body weight regulation 13 , adaptive thermogenesis including fever 14,15 , and aging 16 .…”

Section: Uncoupling Proteinsmentioning

confidence: 99%

Modulation of Ucp2 Expression by P38 - A Link to Cardioprotection

E¹,

Modrianský²

2008

BIOMED PAP

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Background: Discovery of uncoupling protein 2 (UCP2) in 1997 and demonstration of its wide tissue expression has triggered an important question about controlled oxidative phosphorylation uncoupling and the physiological function of this process. Uncoupling protein 2 (UcP2) is a mitochondrial protein that can infl uence the mitochondrial membrane potential and hence the production of reactive oxygen species by mitochondria. It is also thought to be involved in apoptotic signaling pathways and it has been suggested to be important in cardio-and neuroprotection.Methods and results: We examined the recent literature (2003)(2004)(2005)(2006)(2007) in the MedLine database for evidence linking p38, one of the stress-related protein kinases, with modulation of UCP2 expression in the heart. While two reports clearly demonstrate p38 as down-regulating UcP2 expression, only circumstantial evidence exists for cardiomyocytes. Confl icting results on p38-regulated cardiomyocyte survival after ischemia leave an open venue for hypotheses on the diff erential regulation of protein expression, including UCP2.Conclusions: Reviewing the evidence connecting UCP2 and its cytoprotective activities, we propose a tissue specifi c link that may explain the variable infl uence of p38 via modulation of UCP2 expression.

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Reduction of diet-induced obesity in transgenic mice overexpressing uncoupling protein 3 in skeletal muscle

Abstract: Our study shows that 18-fold overexpression of UCP3 mRNA in the skeletal muscle reduced diet-induced obesity. An 18-fold increase of UCP3 mRNA can be attained by physiological or pharmacological stimuli, suggesting that UCP3 has therapeutic potential in the treatment of obesity.

Cited by 57 publications

References 31 publications

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

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

Modulation of Ucp2 Expression by P38 - A Link to Cardioprotection

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