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

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 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.

C-C Chemokine Receptor 2 Inhibitor Improves Diet-Induced Development of Insulin Resistance and Hepatic Steatosis in Mice

“…We previously demonstrated that propagermanium treatment increased the enzymes associated with lipid oxidation including carnithine palmitoyltransferase (CPT) and acyl-CoA oxidase (ACOX) in the muscle and liver of db/db mice 17) . In the present study, we confirmed that propagermanium increased the expression of ACOX and uncoupling protein 3 (UCP3), which contributes to energy expenditure 36,37) , in muscle (supplemental figure). Thus, an increase in plasma adiponectin, lipid oxidation, and energy expenditure in muscle by propagermanium treatment might suppress obesity in DIO mice.…”

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

“…Female adipose-Stra6 Ϫ/Ϫ mice had lower body weights as they got older, whereas male adiposeStra6 Ϫ/Ϫ mice had normal body weights and serum leptin levels up to 24 weeks of age, although leanness in males could emerge at a later age. Sexual dimorphisms have been observed in several mouse models of obesity (55) and diabetes (56,57). Vitamin A metabolism may be important in these sexual dimorphisms, since female mice, but not male mice, with a block in vitamin A metabolism are resistant to the high-fat-diet-induced formation of visceral fat (58).…”

Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice

“…Therefore, metabolic experiments should be carried out on agematched mice. As sex can also influence the phenotype resulting from genetic mutations (Tiraby et al, 2007;Shi et al, 2008;Macotela et al, 2009), it is recommended that studies be conducted on mice from the same sex. If mice from both sexes are used, investigators should attempt to include equal numbers of mice from each sex and make comparisons within same-sex groups, if sexual dimorphisms exist.…”