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PubMed2005

Regulation of uncoupling proteins 2 and 3 in porcine adipose tissue.

This study was performed to determine whether or not uncoupling protein 2 (UCP2) and UCP3 expression in porcine subcutaneous adipose tissue are hormonally regulated in vitro and whether their expression is correlated with changes in metabolic activity. Tissue slices (approximately 100 mg) were placed in 12-well plates containing 1 mL of DMEM/F12 with 25 mM Hepes, 0.5% BSA, pH 7.4. Triplicate slices were incubated with basal medium or hormone supplemented media at 37 degrees C with 95% air/5% CO2. Parallel cultures were maintained for either 2 or 24 h to evaluate metabolic viability of the tissue. Slices were transferred to test tubes containing 1 mL of DMEM/F12 with 25 mM Hepes, 3% BSA, 5.5 mM glucose, 1 microCi 14C-U-glucose/mL and incubated for an additional 2 h at 37 degrees C. Glucose metabolism in 2-h incubations did not differ from 24-h (chronic) incubations, indicating viability was maintained (P>0.05). Expression of UCP2 and UCP3 was assessed in slices following 24h of incubation with various combinations of hormones by semi-quantitative RT-PCR. Expression of UCP2 was induced by leptin (100 ng/mL; P<0.05). Growth hormone (100 ng/mL) inhibited UCP2 expression (P<0.05). Expression of UCP3 was inhibited by growth hormone (100 ng/mL; P<0.05), tri-iodothyronine (10 nM; P<0.05) or leptin (100 ng/mL; P<0.05). Changes in UCP expression could not be associated with overall changes in glucose metabolism by adipose tissue slices in chronic culture.

Adipose Tissue↗

PubMed2001

Uncoupling protein 2 in the brain: distribution and function.

Uncoupling protein 2 (UCP2) mRNA is expressed in a panoply of tissues, including the brain, where it is widely distributed. In the mouse brain, it is expressed in the hypothalamus (suprachiasmatic, paraventricular, dorsomedial, ventromedial and arcuate nuclei), the thalamus (submedius nucleus) and the brain-stem (dorsal motor nucleus of the vagus nerve). In the rat brain, it is also expressed in the hippocampus. The presence of UCP2 mRNA in neurons expressing corticotropin-releasing factor and arginine-vasopressin suggests a role for UCP2 in the control of neuroendocrine and behavioural functions. We have recently demonstrated that UCP2-deficient mice can resist the lethal effect of toxoplasmosis through an enhanced production of reactive oxygen species (ROS) from the macrophages. This finding provides evidence that UCP2 can be part of a mechanism preventing ROS production. UCP2 could therefore be involved in protecting the brain against oxidative stress. The involvement of UCP2 in neuroprotection is also consistent with the recent observation that kainic acid, which promotes Ca(2+) uptake in the glutamate-activated neurons in the hippocampal CA1 field, can induce the UCP2 gene in the activated CA1 cells. The role of UCP2 in neuroprotection warrants further investigation.

Animals↗

PubMed2004

Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients.

Common uncoupling protein 2 (UCP2) promoter polymorphism -866G/A is reported to be associated with its expression in adipose tissue and the risk of obesity in Caucasians. On the other hand, several studies suggested that UCP2 expression in beta-cells is an important determinant of insulin secretion. In the Japanese population, morbid obesity is very rare, and insulin secretion capacity is relatively low as compared with Caucasians. Because UCP2 would link to insulin secretion and obesity, it might explain this ethnic difference. Here, we report that the UCP2 promoter with the A allele showed higher promoter activity in the INS-1 beta-cell line. The frequency of the A allele is higher in our Japanese study than that in Caucasians. Type 2 diabetic patients with the A allele need insulin therapy earlier and showed higher frequency of insulin treatment. Moreover glucose-induced early insulin secretion is significantly lower in patients with the A allele. However, there was no difference in allele frequency between obese and lean type 2 diabetic patients. In conclusion, UCP2 promoter polymorphism -866G/A does not affect obesity in Japanese type 2 diabetic patients but affects its transcription in beta-cells and modulates glucose-induced insulin secretion and eventually insulin requirement in Japanese type 2 diabetic patients. Higher A allele frequency in the Japanese population might partly explain the ethnic difference of insulin secretion capacity.

Aged↗

PubMed2003

Uncoupling protein 2 influences dopamine secretion in PC12h cells.

Uncoupling protein 2 (UCP2) belongs to the UCP family, and is distributed in many organs including the brain. Although UCP2 is known to be related to many functions such as the regulation of insulin secretion or the scavenging of the radicals, the role of UCP2 in the central nervous system remains unclear. In this report, rat UCP2 (rUCP2) and its mutants were overexpressed in the PC12h cells to determine the physiological roles played by UCP2 in neural cells and to elucidate the mechanisms that regulate these functions. It was found that rUCP2 was activated by the stimulation of the cAMP-protein kinase A (PKA) cascade. Moreover, the activation of rUCP2 suppressed intracellular ATP levels and inhibited the cAMP-dependent increase of dopamine secretion. Thus, UCP2 appears to be regulated by the excitatory stimulus via the cAMP-PKA cascade and serves to negatively control the synaptic output by reducing intracellular ATP levels.

Adenosine Triphosphate↗

PubMed1999

Lack of skeletal muscle uncoupling protein 2 and 3 mRNA induction during fasting in type-2 diabetic subjects.

Skeletal muscle uncoupling protein 2 and 3 (UCP-2 and UCP-3) mRNA levels are increased during calorie restriction in lean and nondiabetic obese subjects. In this work, we have investigated the effect of a 5-day hypocaloric diet (1,045 kJ/day) on UCP-2 and UCP-3 gene expression in the skeletal muscle of type-2 diabetic obese patients. Before the diet, UCP-2 and UCP-3 mRNA levels were more abundant in diabetic than in nondiabetic subjects. The long (UCP-3(L)) and short (UCP-3(S)) forms of UCP-3 transcripts were expressed at similar levels in nondiabetic subjects, but UCP-3(S) transcripts were twofold more abundant than UCP-3(L) transcripts in the muscle of diabetic patients. Calorie restriction induced a two- to threefold increase in UCP-2 and UCP-3 mRNA levels in nondiabetic patients. No change was observed in type-2 diabetic patients. Variations in plasma nonesterified fatty acid level were positively correlated with changes in skeletal muscle UCP-3(L) (r = 0.6, P < 0.05) and adipose tissue hormone-sensitive lipase (r = 0.9, P < 0.001) mRNA levels. Lack of increase in plasma nonesterified fatty acid level and in hormone-sensitive lipase upregulation in diabetic patients during the diet strengthens the hypothesis that fatty acids are associated with the upregulation of uncoupling proteins during calorie restriction.

Carrier Proteins↗

PubMed2004

Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes.

We searched for the presence of uncoupling protein genes so far unknown in marsupials and monotremes and identified uncoupling protein 2 (UCP2) and UCP3 full-length cDNAs in libraries constructed from the marsupials Antechinus flavipes and Sminthopsis macroura. Marsupial UCP2 is 89-90% identical to rodent UCP2, whereas UCP3 exhibits 80% identity to mouse UCP3. A phylogenetic tree including all known UCPs positions the novel marsupial UCP2 and UCP3 at the base of the mammalian orthologs. In the 5'-untranslated region of UCP2 a second open reading frame encoding for a 36-amino acid peptide was identified which is highly conserved in all vertebrate UCP2 transcripts. Analysis of tissue specificity in A. flavipes with homologous cDNA probes revealed ubiquitous presence of UCP2 mRNA and striated muscle specificity of UCP3 mRNA resembling the known expression pattern in rodents. Neither UCP2 nor UCP3 gene expression was stimulated in adipose tissue and skeletal muscle of cold exposed A. flavipes. However, UCP3 mRNA expression was upregulated 6-fold in heart and 2.5-fold in skeletal muscle as reported for rodents in response to fasting. Furthermore, UCP3 mRNA seems to be coregulated with PDK4 mRNA, indicating a relation to enhanced lipid metabolism. In contrast, UCP2 gene expression was not regulated in response to fasting in adipose tissue and skeletal muscle but was diminished in the lung and increased in adipose tissue. Taken together, the sequence analysis, tissue specificity and physiological regulation suggest a conserved function of UCP2 and UCP3 during 130 million years of mammalian evolution.

Amino Acid Sequence↗

PubMed2006

Uncoupling protein 2 negatively regulates neurite extensions in PC12h cells.

Uncoupling protein 2 (UCP2) distributes in many organs including the brain. Though recent reports suggest that UCP2 is involved in the neuroprotection and the regulation of neurosecretion, the roles of UCP2 in the central nervous systems remain largely unclear. In order to clarify the significance of UCP2 in the brain especially at developmental stage, subcellular localizations of rat UCP2 (rUCP2) in the developing cerebellar Purkinje cells were immunochemically examined. The rUCP2-like immunoreactivities observed axon or its terminal during axonal maturation. This result implies that rUCP2 contributes to the neurite development. In the PC12h cells overexpressing rUCP2 or active mutant of rUCP2, the neurite outgrowth was significantly inhibited along with a reduction of cellular ATP level. These findings suggest a possibility that UCP2 is involved in negative regulation of neurite extensions through repression of the energy supply.

Animals↗

PubMed2006

Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis.

Uncoupling protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expressed in many tissues, including immune cells. UCP2 prevents oxidative stress by reducing reactive oxygen species. Using UCP2-deficient mice, it was shown that UCP2 is involved in the regulation of insulin secretion, in the resistance to infection, and in atherosclerosis. Here, we investigated the role of UCP2 in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Immunized C57BL/6J UCP2-deficient mice showed a slightly delayed onset during experimental autoimmune encephalomyelitis (13.0 +/- 0.6 versus 11.5 +/- 0.8 in wild-type controls) and developed significantly higher disease scores than littermate controls (maximum disease score of 2.9 +/- 0.2 versus 1.7 +/- 0.2, P = 0.001). Higher levels of infiltrating T cells into the spinal cord meninges and parenchyma were observed. The T-cell proliferative response to the specific antigen was increased in UCP2-deficient mice compared with littermate controls, and CD4 cells of UCP2 knockout mice produced significantly higher levels of pro-inflammatory cytokines, eg, tumor necrosis factor-alpha and interleukin-2, resulting from a Th1 response. Mice lacking UCP2 also developed a higher B-cell response. Concomitantly, CD4 and CD8 cells of the UCP2-deficient mice showed increased production of reactive oxygen species. These results suggest a protective function of UCP2 in chronic inflammatory diseases such as multiple sclerosis.

Animals↗

PubMed2006

Genomic structure and expression of uncoupling protein 2 genes in rainbow trout (Oncorhynchus mykiss).

BACKGROUND: Uncoupling protein 2 (UCP2) belongs to the superfamily of mitochondrial anion carriers that dissociate the respiratory chain from ATP synthesis. It has been determined that UCP2 plays a role in several physiological processes such as energy expenditure, body weight control and fatty acid metabolism in several vertebrate species. We report the first characterization of UCP2s in rainbow trout (Oncorhynchus mykiss). RESULTS: Two UCP2 genes were identified in the rainbow trout genome, UCP2A and UCP2B. These genes are 93% similar in their predicted amino acid sequences and display the same genomic structure as other vertebrates (8 exons and 7 introns) spanning 4.2 kb and 3.2 kb, respectively. UCP2A and UCP2B were widely expressed in all tissues of the study with a predominant level in macrophage-rich tissues and reproductive organs. In fry muscle we observed an increase in UCP2B expression in response to fasting and a decrease after refeeding in agreement with previous studies in human, mouse, rat, and marsupials. The converse expression pattern was observed for UCP2A mRNA which decreased during fasting, suggesting different metabolic roles for UCP2A and UCP2B in rainbow trout muscle. Phylogenetic analysis including other genes from the UCP core family located rainbow trout UCP2A and UCP2B with their orthologs and suggested an early divergence of vertebrate UCPs from a common ancestor gene. CONCLUSION: We characterized two UCP2 genes in rainbow trout with similar genomic structures, amino acid sequences and distribution profiles. These genes appeared to be differentially regulated in response to fasting and refeeding in fry muscle. The genomic organization and phylogeny analysis support the hypothesis of a common ancestry between the vertebrate UCPs.

Amino Acid Sequence↗

PubMed2000

Uncoupling proteins 2 and 3 interact with members of the 14.3.3 family.

Uncoupling proteins (UCPs) are members of the superfamily of the mitochondrial anion carrier proteins (MATP). Localized in the inner membrane of the organelle, they are postulated to be regulators of mitochondrial uncoupling. UCP2 and 3 may play an important role in the regulation of thermogenesis and, thus, on the resting metabolic rate in humans. To identify interacting proteins that may be involved in the regulation of the activity of UCPs, the yeast two-hybrid system was applied. Segments of hUCP2 containing the hydrophilic loops facing the intermembrane space, or combinations of these, were used to screen an adipocyte activation domain (AD) fusion library. The 14.3.3 protein isoforms theta, beta, zeta were identified as possible interacting partners of hUCP2. Screening of a human skeletal muscle AD fusion library, on the other hand, yielded several clones all of them encoding the gamma isoform of the 14.3.3 family. Mapping experiments further revealed that all these 14.3.3 proteins interact specifically with the C-terminal intermembrane space domain of both hUCP2 and hUCP3 whereas no interactions could be detected with the C-terminal part of hUCP1. Direct interaction between UCP3 and 14.3.3 theta could be demonstrated after in vitro translation by coimmunoprecipitation. When coexpressed in a heterologous yeast system, 14.3.3 proteins potentiated the inhibitory effect of UCP3 overexpression on cell growth. These findings suggest that 14.3.3 proteins could be involved in the targeting of UCPs to the mitochondria.

14-3-3 Proteins↗

PubMed2005

Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia.

Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are up-regulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxia-reoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent anti-oxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells.

Animals↗

PubMed1998

Genomic organization and promoter function of the mouse uncoupling protein 2 (UCP2) gene.

We cloned and characterized the mouse uncoupling protein 2 (UCP2) gene and its promoter region. The gene spans approximately 6.3 kb and contains eight exons and seven introns. Two short exons are located in the 5' untranslated region, and each of the remaining exons encodes one of the transmembrane domains. 3'-RACE analysis showed that a polyadenylation signal 257 bp downstream from the stop codon was functional. Primer extension analysis indicated a single transcriptional start site 369 bp upstream from the translational start site. The promoter region lacks both TATA and CAAT boxes but is GC-rich. A construct containing 1250 bp of the promoter region showed significant activity in all 6 cell lines examined, and the region between -160 and -678 bp exhibited strong positive regulatory activity. These features of the UCP2 gene are different from those of the UCP1 gene and may contribute to its ubiquitous expression.

Amino Acid Sequence↗

PubMed2006

The uncoupling protein 2 modulates the cytokine balance in innate immunity.

The uncoupling protein 2 (UCP2) is located in the inner mitochondrial membrane and downregulates the production of reactive oxygen species (ROS). Recent data suggested a role for UCP2 in the immune response. We analyzed further this hypothesis during acute Listeria monocytogenes infection in mice. Death of infected Ucp2(-/-) mice was delayed in comparison with Ucp2(+/+), suggesting a role of UCP2 in the early step of the immune response. In vitro, the higher resistance of Ucp2(-/-) mice was not associated with a better control of bacterial growth by macrophages. In vivo, a significant increase of recruited phagocytes was observed in the spleen of Ucp2(-/-) mice. This was associated with a higher level of ROS in the spleen. Upregulation of pro-inflammatory cytokines IFNgamma, IL6, and IL1beta and of the chemokine MCP1 was observed in Ucp2(-/-) mice 4 days after infection, preceded by a decrease of the anti-inflammatory cytokine IL10 production. Present data highlight that, in an acute model of infection, UCP2 modulates innate immunity, via the modulation of ROS production, cytokine and chemokine production and consequently phagocyte recruitment.

Animals↗

PubMed1999

Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets.

Uncoupling protein 2 (UCP-2) mRNA expression has been shown to be altered by metabolic conditions such as obesity in humans, but its functional significance is unknown. The expression of UCP-2 mRNA and protein in normal rat islets was established by reverse transcriptase-polymerase chain reaction and immunocytochemistry in pancreatic islets and tissue, respectively. Intense immunostaining of UCP-2 correlated with insulin-positive ,-cells. Overexpression of UCP-2 in normal rat islets was accomplished by infection with an adenovirus (AdEGI-UCP-2) containing the full-length human UCP-2 coding sequence. Induction of the AdEGI-UCP-2 gene resulted in severe blunting of glucose-stimulated insulin secretion (GSIS) without affecting islet insulin content or the ability of the calcium ionophore A23187 to increase insulin secretion from AdEGI-UCP-2-expressing islets. Therefore, UCP-2 overexpression affects signal transduction proximal to Ca2+-mediated steps, including exocytosis. Insulin secretion from single beta-cells to 16.5 mmol/l glucose examined by reverse hemolytic plaque assay was nearly ablated if UCP-2 was overexpressed. Thus, a direct, causal relationship between overexpression of UCP-2 and inhibition of GSIS in normal islets has been established. These data suggest that increased expression of UCP-2 has the potential to cause the lack of a glucose effect on insulin secretion in type 2 diabetes.

Adenoviridae↗

PubMed2003

Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation.

The mitochondrial uncoupling protein 2 (UCP2) is expressed in spleen, lung, intestine, white adipose tissue, and immune cells. Bone marrow transplantation in mice was used to assess the contribution of immune cells to the expression of UCP2 in basal condition and during inflammation. Immune cells accounted for the total amount of UCP2 expression in the spleen, one-third of its expression in the lung, and did not participate in its expression in the intestine. LPS injection stimulated UCP2 expression in lung, spleen, and intestine in both immune and non-immune cells. Successive injections of LPS and dexamethasone or N-acetyl-cysteine prevented the induction of UCP2 in all three tissues, suggesting that oxygen free radical generation plays a role in UCP2 regulation. Finally, both previous studies and our data show that there is down-regulation of UCP2 in immune cells during their activation in the early stages of the LPS response followed by an up-regulation in UCP2 during the later stages to protect all cells against oxidative stress.

Acetylcysteine↗

PubMed2005

Up-regulation of uncoupling protein 2 by cyanide is linked with cytotoxicity in mesencephalic cells.

Uncoupling protein 2 (UCP-2) regulates mitochondrial function by increasing proton leak across the inner membrane to dissociate respiration from ATP synthesis and reduce reactive oxygen species generation. A number of studies have shown that UCP-2 expression protects cells from oxidative stress mediated injuries. In the current study, we show UCP-2-mediated reduction in mitochondrial function contributes to the mitochondrial dysfunction and the necrotic death of primary cultured mesencephalic cells (MCs) after exposure to cyanide, a complex IV inhibitor. The necrotic cell death was directly related to the level of mitochondrial dysfunction, as shown by reduction in ATP levels and decreased mitochondrial membrane potential. Treatment with cyanide for 6 h or longer upregulated UCP-2 expression. Blockade of up-regulation with a transcription or a translational inhibitor reduced the response to cyanide. Knockdown with RNAi or transfection with a UCP-2 dominant-negative interfering mutant reduced the cyanide-induced mitochondrial dysfunction and cell death, showing that constitutive expression of UCP-2 plays a role in the response to cyanide. Overexpression of UCP-2 by transfection with human full-length cDNA potentiated the cyanide toxicity. These findings indicate that UCP-2 can serve as a regulator of mitochondria-mediated necrotic cell death, in which enhanced expression can increase the vulnerability of primary MCs to injury due to complex IV-mediated inhibition by cyanide.

Adenosine Triphosphate↗

PubMed2005

Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells.

A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating beta-cell UCP2 gene expression have been established in rodents only. We show here that the underlying sequence motifs are not conserved in the human gene and provide evidence for regulatory mechanisms involving the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha). PGC-1alpha potentiates thyroid hormone (T(3))-mediated transcriptional activation of the human UCP2 gene in INS-1E cells. Two thyroid hormone response elements (TREs) located at -322/-317 (TRE1) and -170/-165 (TRE2) were identified, and mutation of either TRE1 or TRE2 abrogated the stimulatory effect of T(3) treatment. Furthermore, two E-box motifs at -911/-906 (E1) and -743/-738 (E2) are involved in the regulation of UCP2 gene expression by sterol regulatory element binding protein isoforms (SREBP)-1a, -1c, and -2. Mutational analysis revealed that the presence of either E1 or E2 is sufficient to mediate activation of UCP2 gene transcription by nuclear active SREBPs. PGC-1alpha coactivates liver X receptor-mediated expression of SREBP-1c as well as dexamethasone-stimulated SREBP-2 expression in INS-1E cells. These transcriptional responses are antagonized by orphan nuclear receptor short heterodimer partner overexpression, which might explain its positive effects on glucose-stimulated insulin secretion in beta-cells overexpressing UCP2. We also provide evidence that despite a lack of sequence homology within the regulatory region, the principal mechanisms regulating UCP2 gene expression are similar in rats and humans, being consistent with a role for UCP2 as a modulator of insulin secretion in humans.

Animals↗

PubMed1998

High expression of uncoupling protein 2 in foetal liver.

To assess the putative role of mitochondrial uncoupling protein 2 (UCP2) during perinatal development, its expression was analysed in mice and rats. Expression was detected in a large range of foetal tissues. A unique developmental pattern of UCP2 expression was found in liver, where the level of UCP2 mRNA was about 30-fold higher in foetuses than in adults (mice data), and started to decline immediately after birth. Neither UCP1 nor UCP3 mRNA was expressed in foetal liver. As in adult liver, immunohistochemical analysis suggested exclusive localisation of UCP2 in the monocyte/macrophage cells. Our results indicate a role of UCP2 in haematopoietic system development.

Animals↗