Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice

Li, Bing; Nolte, Lorraine A.; Ju, Jeong-Sun; Han, Dong; Coleman, Trey; Holloszy, John O.; Semenkovich, Clay F.

doi:10.1038/80450

Cited by 275 publications

(270 citation statements)

References 44 publications

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“…Ectopic expression of UCP1 in SM has been achieved by three independent groups, using different promoters in transgenic constructs (Li et al 2000;Couplan et al 2002;Klaus et al 2005). Several transgenic lines were generated and investigated (Li et al 2000;Couplan et al 2002).…”

Section: Skeletal Musclementioning

confidence: 99%

“…Several transgenic lines were generated and investigated (Li et al 2000;Couplan et al 2002). Studies of these transgenic mice, all of them containing UCP1 cDNA, provide the unique opportunity to analyze the ''true'' effects of ectopic UCP1 in SM independent of mouse background strain, animal maintenance, or possible artifacts due to the insertion site of the transgene.…”

Section: Skeletal Musclementioning

confidence: 99%

“…In the model first described by Li et al (2000), UCP1 expression was driven by the rat myosin light chain 2 promoter resulting in two independent lines of mice on a C57Bl/6 9 CBA hybrid background: Ucp-L and Ucp-H, with low and high expression of UCP1 gene in SM but no other tissues. Low expression corresponded to *1% of UCP1 content in muscle mitochondria compared to BAT mitochondria in heterozygous mice.…”

Section: Skeletal Musclementioning

confidence: 99%

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Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

et al. 2011

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Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

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Section: Skeletal Musclementioning

confidence: 99%

Section: Skeletal Musclementioning

confidence: 99%

Section: Skeletal Musclementioning

confidence: 99%

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Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

et al. 2011

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“…Although none of the UCP ±/± mice (1, 2 or 3) is obese [10, 48, 111, 140, 141] it remains to be determined how UCP2 interacts with other potential energy monitoring molecules to participate in weight homeostasis. Of interest are data showing that mice with skeletal muscle-specific induction of UCP3 have decreased body weight despite normal [142] or increased food intake [143]. The metabolic rate is increased, as is insulin sensitivity and glucose uptake, whereas adipose tissue mass is reduced by about 50 % [143].…”

Section: Relation Of Ucp2 With Metabolic Diseasesmentioning

confidence: 99%

Uncoupling protein-2: evidence for its function as a metabolic regulator

2002

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Uncoupling protein-2 (UCP2) was discovered in 1997 but a definitive understanding of its functions has so far eluded investigators. Potential roles include regulating fat metabolism directly and indirectly via effects on insulin secretion. Also, UCP2 could also negatively modulate the production of reactive oxygen species (ROS). Although evidence in support of these functions is correlational, research on UCP2 mechanisms of action has recently been published. Studies of polymorphisms in the uncoupling protein-2 gene have not been included in detail here but are reviewed elsewhere [1,2]. For an in depth discussion of the uncoupling protein family of proteins, readers are referred to recent reviews [1, 3]. Chemical properties of uncoupling proteinsMitochondrial metabolism generates more than 90 % of the ATP required by organisms for routine cellular processes. The efficiency of ATP formation could be altered by demand, by drugs or by pathological processes. Uncoupling agents dissociate fuel oxidation in the electron transport chain of mitochondria from phosphorylation of substrate, namely ADP. Normally, glucose-derived NADH and FADH 2 stimulate Diabetologia (2002) AbstractUncoupling protein-2, discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as carriers. The function(s) of uncoupling protein-2 have not yet been definitively described. However, mounting evidence suggests that uncoupling protein-2 could act in multiple tissues as a regulator of lipid metabolism. A role as a modulator of reactive oxygen species as a defence against infection is also postulated. In this review, a brief overview of the general and specific properties of uncoupling protein-2 is given and evidence for metabolic and immune regulatory functions is summarized.Uncoupling protein-2 could have particular importance in the regulation of lipid metabolism in adipose tissue and skeletal muscle. In addition, its ability to inhibit insulin secretion could also promote fat utilization over storage. Inhibition by uncoupling protein-2 of reactive oxygen species formation in macrophages and other tissues could have implications for regulation of immune function. The possibility of functions of uncoupling protein-2 in other tissues such as the brain are beginning to emerge. [Diabetologia (2002) 45: 174±187]

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“…Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle has been shown to result in a phenotype characterized by increased energy expenditure, reduced body weight, reduced fat mass, improved glucose tolerance, decreased muscle energy efficiency, and altered substrate oxidation (Couplan et al 2002;Klaus et al 2005;Li et al 2000). UCP1-tg mice express the murine UCP1 gene in striated skeletal muscle, driven by the human skeletal actin promoter (Klaus et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

et al. 2015

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Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia [300 mg/dl) was fully prevented in both F1-and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue.

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Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice

Cited by 275 publications

References 44 publications

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

Uncoupling protein-2: evidence for its function as a metabolic regulator

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

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