Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production

Arsenijevic, Denis; Onuma, Hiroki; Pecqueur, Claire; Raimbault, Serge; Manning, Brian S.; Miroux, Bruno; Couplan, Elodie; Alves-Guerra, Marie-Clotilde; Goubern, Marc; Surwit, Richard S.; Bouillaud, Frédéric; Richard, Denis; Collins, Sheila; Ricquier, Daniel

doi:10.1038/82565

Cited by 985 publications

(900 citation statements)

References 27 publications

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“…4,7,8 High expression of UCP2 has been reported in cells of the immune system, and the expression was affected by the -866 G variation in vivo and in vitro. 4,9,10 The -866 G allele decreasing the UCP2 expression is associated with increased risk to chronic inflammatory diseases. This observation is consistent with findings in mouse studies, where UCP2-deficient mice were more susceptible to experimental autoimmune encephalomyelitis (EAE) and showed stronger immune responses to infections than wild-type controls.…”

Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

“…This observation is consistent with findings in mouse studies, where UCP2-deficient mice were more susceptible to experimental autoimmune encephalomyelitis (EAE) and showed stronger immune responses to infections than wild-type controls. 9,11 As the A allele increasing the gene expression is associated with a decreased risk to diseases, it suggests that the UCP2 protein play a protective role in chronic inflammatory diseases.…”

Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

“…There is growing evidence that ROS generated by the mitochondria could be important for immune responses. The ROS production in macrophages from UCP2-deficient mice is B80% higher than in wild-type mice, and the deficiency of the UCP2 gene increases the susceptibility to EAE, a mouse model for MS. 9,11 In addition, mouse mtDNA variations affecting mitochondrial ROS production are associated with susceptibility to autoimmune diabetes and EAE. 14,15 This indicates that mitochondrial ROS production could be a regulator of susceptibility to chronic inflammatory diseases.…”

Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

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Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

Wieczorek

Franke³

et al. 2009

Genes Immun

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Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

Section: Association Of Ucp2 à866 G/a Polymorphism X Yu Et Almentioning

confidence: 99%

See 1 more Smart Citation

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

Wieczorek

Franke³

et al. 2009

Genes Immun

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“…Based on their similarity of sequence, UCP2 and UCP3 were first suggested to play a role in regulated thermogenesis [2]. Later studies demonstrated that this may not be the case [3] and now evidence is accumulating in favour of a role in reducing the production of reactive oxygen species (ROS) by the mitochondria [4,5].…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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“…The results from these mice also suggest that UCP2 -3 may be important for the regulation of ROS. The UCP2 null mice seem to produce less ROS than the wild-type mice (Arsenijevic et al, 2000), and the UCP3 null mice have increased production of ROS (Vidal-Puig et al, 2000). Recently, Echtay et al (2002) showed that superoxide activates UCP1 -3 proteins and the uncoupling is induced by fatty acids.…”

Section: Discussionmentioning

confidence: 99%

Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy

Lindholm

Klannemark

Agardh

et al. 2004

Journal of Diabetes and its Complications

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Increased production of reactive oxygen species (ROS) has been suggested as a cause of diabetic complications. Uncoupling proteins (UCPs) have been ascribed a role in reducing the formation of ROS, and genetic variation in genes encoding for UCPs could thus be putative candidate genes for diabetic nephropathy. To test this hypothesis we searched for association between the A ! G ( À 3862) variant in UCP1, the insertion/deletion (I/D) polymorphism in exon 8 in UCP2, and the C ! T ( À 55) polymorphism in UCP3 and diabetic nephropathy in 218 diabetic patients with normal urinary albumin excretion rate (AER), 216 with micro-or macroalbuminuria, and in 106 control subjects without a family history of diabetes. We did not find any association between the different polymorphisms and diabetic nephropathy, nor did we observe any difference in AER among carriers of different UCP1 -3 genotypes. We could, however, confirm the reported association between BMI and the UCP3 À 55 C ! T polymorphism; patients carrying the T allele had higher BMI than patients homozygous for the C allele (26.4 ± 4.2 vs. 25.3 ± 4.3 kg/m 2 ; P = .01). We conclude that studied polymorphisms in the UCP1 -3 genes do not play a major role in the development of micro-or macroalbuminuria in Scandinavian diabetic patients.

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Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production

Cited by 985 publications

References 27 publications

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy

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