HGNC Approved Gene Symbol: UCP2
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:73,974,672-73,983,202 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | {Obesity, susceptibility to, BMIQ4} | 607447 | 3 |
The mitochondrial protein called uncoupling protein (UCP1; 113730) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. Fleury et al. (1997) noted that this pathway has been implicated in the regulation of body temperature, body composition, and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and in humans living in a thermoneutral environment, i.e., one in which an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature, as there is little brown adipose tissue present in the adults. Fleury et al. (1997) discovered a gene that codes for a novel uncoupling protein they designated UCP2, which has 59% amino acid identity to UCP1. It was found to have properties consistent with a role in diabetes and obesity (see 601665). In comparison with UCP1, UCP2 had a greater effect on the mitochondrial membrane potential when expressed in yeast. Compared to UCP1, UCP2 is widely expressed in adult human tissues, including tissue rich in macrophages, and it is upregulated in white fat in response to fat feeding.
Flier and Lowell (1997) characterized the work reported by Fleury et al. (1997) as a 'major breakthrough towards understanding the molecular basis for energy expenditure.' They considered these findings likely to have important implications for the causes and treatment of human obesity.
Bouchard et al. (1997) studied the linkage relationships between 3 microsatellite markers that encompass the UCP2 gene location on 11q13 with resting metabolic rate (RMR), body mass index, percentage body fat, and fat mass in 640 individuals from 155 pedigrees in the Quebec family study. Suggestive evidence of linkage led them to conclude that the 3 markers encompassing the UCP2 locus and spanning a 5-cM region on 11q13 are linked to resting energy expenditure in adult humans. The evidence was strong enough, in their opinion, to warrant a search for DNA sequence variation in the gene itself.
Millet et al. (1997) observed an increase in the levels of UCP2 and UCP3 (602044) mRNA in skeletal muscle and adipose tissue from both lean and obese individuals undergoing fasting. They suggested that the increase indicates a role for these proteins in the metabolic adaptation to fasting. The similar induction of gene expression observed during fasting in lean and obese subjects show that there is no major alteration of UCP2 and UCP3 gene regulation in adipose tissue and skeletal muscle of obese subjects. UCP2 is widely expressed in human tissues, whereas UCP3 expression seems to be restricted to skeletal muscle, an important site of thermogenesis in humans.
Hepatic hematopoiesis is prominent during fetal life and ceases around birth. Brauner et al. (2001) characterized hepatic hematopoiesis in humans around birth and identified cells expressing UCP2. Hematopoiesis was evaluated histologically in the liver of 22 newborns (mostly very premature neonates), who died between 45 minutes and 140 days after birth, and 1 fetus. UCP2 expression was characterized by Northern blots, immunoblotting, immunohistochemistry, and by in situ hybridization. The number of hematopoietic cells started to decrease rapidly at birth, irrespective of gestational age (23 to 40 weeks) of neonates. A similar decline was observed for UCP2 expression, which was relatively high in fetal liver. UCP2 was detected only in myeloid cells (mainly in Kupffer cells), but not in hepatocytes, although sepsis or other pathologies occurred in the critically ill newborns. Kupffer cells represent the major site of mitochondrial UCP2 expression in the human newborn. UCP2 may be essential for the differentiation and function of macrophages and serve as a marker for these cells in human liver during the perinatal period.
UCP1 diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose by catalyzing a regulated leak of protons across the inner membrane. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species (ROS), which are important mediators of oxidative damage. Echtay et al. (2002) demonstrated that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2, and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. Superoxide-induced uncoupling correlates with the tissue expression of UCPs and appears in mitochondria from yeast expressing UCP1. Skeletal muscle mitochondria express only UCP3h; therefore superoxide-induced uncoupling is absent in the skeletal muscle of UCP3 knockout mice. Echtay et al. (2002) concluded that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of ROS inside mitochondria.
Neuronal cell death usually occurs after a certain period of ischemia, suggesting that neurons are able to sustain sublethal damage up to a threshold level, presumably through endogenous protective pathways. Using subtractive cDNA libraries and cDNA array analysis of CA1 fields of rat hippocampi at multiple times after ischemic preconditioning, Mattiasson et al. (2003) identified UCP2 as an inducible neuroprotective protein. In mice overexpressing human UCP2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurologic recovery was enhanced. In cultured cortical neurons, UCP2 reduced cell death and inhibited caspase-3 (600636) activation induced by oxygen and glucose deprivation. In isolated mitochondria, UCP2 shifted the release of ROS from the mitochondrial matrix to the extramitochondrial space. Mattiasson et al. (2003) suggested that UCP2 is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.
Sullivan et al. (2003) noted that, in rats, the immature brain is remarkably resistant to seizure-induced excitotoxic cell death compared to adults. They found that seizures did not increase the formation of ROS in neonatal brain because of the presence of high levels of UCP2, which mediates uncoupling in mitochondria (see also Echtay et al., 2002). UCP2 expression and function were increased in neonatal brain by the fat-rich diet of maternal milk, and Sullivan et al. (2003) found that dietary restriction of free fatty acids rendered immature rat limbic neurons vulnerable to seizure-induced neuronal injury.
Wisloff et al. (2005) hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for cardiovascular disease risk. After 11 generations, rats with low aerobic capacity scored higher on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Wisloff et al. (2005) found that the amount of PPARG (601487), PPARG coactivator-1-alpha (PPARGC1A; 604517), ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2; 191329), cytochrome c oxidase subunit I (MTCO1; 516030), uncoupling protein-2 (UCP2), and ATP synthase H(+)-transporting mitochondrial F1 complex (F1-ATP synthase; see 108729) were markedly reduced in the low capacity runner rats in comparison with the high capacity runners. The uniform decline in these proteins was consistent with the hypothesis that reduced aerobic metabolism plays a causal role in the development of the differences between the low capacity runner and high capacity runner rats. Wisloff et al. (2005) concluded that impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.
Parton et al. (2007) disrupted glucose sensing in glucose-excited proopiomelanocortin (POMC; 176830) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene, 600937) that prevents ATP-mediated closure of potassium-ATP channels. They showed that this genetic manipulation impaired the whole body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiologic control of blood glucose. Parton et al. (2007) also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves UCP2, a mitochondrial protein that impairs glucose-stimulated production. UCP2 negatively regulates glucose sensing in POMC neurons. Parton et al. (2007) found that genetic deletion of UCP2 prevented obesity-induced loss of glucose sensing, and that acute pharmacologic inhibition of UCP2 reverses loss of glucose sensing. Parton et al. (2007) concluded that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
Andrews et al. (2008) showed that ghrelin (605353) initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on UCP2. Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY (162640)/AgRP (602311) neurons, for ghrelin-triggered synaptic plasticity of POMC neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK (see 602739), CPT1 (600528), and free radicals that are scavenged by UCP2. Andrews et al. (2008) concluded that their results revealed a signaling modality connecting mitochondria-mediated effects of G protein-coupled receptors on neuronal function and associated behavior.
By immunohistochemical analysis of dispersed and intact mouse pancreatic islets and mouse pancreatic cell lines, Diao et al. (2008) found that alpha cells expressed significantly higher levels of Ucp2 than did beta cells. Alpha cells also showed greater Ucp2-dependent mitochondrial uncoupling compared with beta cells, which was accompanied by a lower oxidative phosphorylation efficiency. Conversely, reducing Ucp2 activity in alpha cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, suppression of Ucp2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in Ucp2-knockout mice. Ucp2 also appeared to be cytoprotective of islet cells, with Ucpp2-knockout alpha cells being more sensitive than wildtype cells to toxic stimuli.
Park et al. (2011) showed that the mitochondrial membrane potential of the phagocyte critically controls engulfment capacity, with lower potential enhancing engulfment and vice versa. The mitochondrial membrane protein Ucp2, which acts to lower the mitochondrial membrane potential, was upregulated in phagocytes engulfing apoptotic cells. Loss of Ucp2 reduced phagocytic capacity, whereas Ucp2 overexpression enhanced engulfment. Mutational and pharmacologic studies indicated a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-deficient mice were impaired in phagocytosis in vitro, and Ucp2-deficient mice showed profound in vivo defects in clearing dying cells in the thymus and testes. Park et al. (2011) concluded that the mitochondrial membrane potential and Ucp2 are key molecular determinants of apoptotic cell clearance.
Pecqueur et al. (1999) determined that the UCP2 gene contains 8 exons and spans 8 kb. Exons 1 and 2 are not translated. The promoter region does not contain a TATA box or a CAAT box, but it is GC rich, unlike UCP1.
Fleury et al. (1997) mapped the UCP2 gene to human 11q13 by using 2 independent sequence tagged sites derived from human UCP2 clones. They also mapped the mouse homolog Ucp2 to murine chromosome 7, tightly linked to the 'tubby' mutation (601197), in an area of homology of synteny to 11q13. Furthermore, the chromosomal mapping of UCP2 was coincident with quantitative trait loci (QTLs) for obesity in at least 3 independent mouse models, one congenic strain, and human insulin-dependent diabetes locus-4 (600319).
Pecqueur et al. (1999) determined that the UCP2 gene is located 7 kb downstream of the UCP3 gene.
The UCP2-UCP3 gene cluster maps to 11q13 in humans. Walder et al. (1998) explored the possibility that polymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing showed 3 polymorphisms informative for association studies: an ala-to-val substitution in exon 4 of UCP2, a 45-bp insertion/deletion in the 3-prime untranslated region of exon 8 of UCP2, and a C-to-T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, full-blooded, nondiabetic Pima Indians were typed for these polymorphisms by direct sequencing. The 3 sites were in linkage disequilibrium with each other (P = less than 0.00001). The UCP2 variants were associated with metabolic rate during sleep. Heterozygotes for UCP2 variants had higher metabolic rates than homozygotes. The UCP3 variant was not significantly associated with metabolic rate or obesity. In a further 790 full-blooded Pima Indians, there was no significant association between the insertion/deletion polymorphism and body mass index (BMI). However, when only individuals more than 45 years of age were considered, heterozygotes (subjects with the highest sleeping metabolic rate) had the lowest BMI (P = 0.04). Walder et al. (1998) concluded that UCP2 (or UCP3) contributes to variation in metabolic rate in young Pima Indians which may contribute to overall body fat content later in life.
Esterbauer et al. (2001) showed that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, they found a modest but significant reduction in obesity prevalence associated with the less-common allele. They confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area (Salzburg, Austria). Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.
Enerback et al. (1997) determined the role of UCP in the regulation of body mass by targeted inactivation of the UCP gene in mice. They found that UCP-deficient mice consumed less oxygen after treatment with a beta-3-adrenergic receptor agonist and that they were sensitive to cold, indicating that thermoregulation was defective. However, this deficiency caused neither hyperphagia nor obesity in mice fed on either a standard or a high-fat diet. Enerback et al. (1997) proposed that the loss of UCP may be compensated by UCP2, a homolog of UCP that is ubiquitously expressed and is induced in the brown fat of UCP-deficient mice.
As Ucp2 is widely expressed in mammalian tissues, uncouples respiration, and resides within a region of genetic linkage to obesity, a role in energy dissipation had been proposed. Arsenijevic et al. (2000) demonstrated, however, that mice lacking Ucp2 following targeted gene disruption were not obese and had a normal response to cold exposure or high-fat diet. Expression of Ucp2 is normally robust in spleen, lung, and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. In this connection, Arsenijevic et al. (2000) found that Ucp2 -/- mice were completely resistant to infection with Toxoplasma gondii, in contrast with the lethality observed in wildtype littermates. Macrophages from the Ucp2-null mice generated more ROS than wildtype mice in response to T. gondii, and had a 5-fold greater toxoplasmacidal activity in vitro compared with wildtype mice, which was absent in the presence of a quencher of ROS. Their results indicated a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
Zhang et al. (2001) assessed the role of UCP2 in regulating insulin secretion. Ucp2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, Ucp2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Ob/ob mice lacking Ucp2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results established UCP2 as a key component of beta-cell glucose sensing and as a critical link between obesity, beta-cell dysfunction, and type II diabetes.
Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type II diabetes. UCP2, by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak (Echtay et al., 2002). Because obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic beta cells, Krauss et al. (2003) hypothesized that a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced beta cell dysfunction. They demonstrated that in mice, endogenously produced mitochondrial superoxide activated Ucp2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness was prevented by reduction of mitochondrial superoxide production or gene knockout of Ucp2. Importantly, reduction of superoxide had no beneficial effect in the absence of Ucp2, and superoxide levels were increased further in the absence of Ucp2, demonstrating that the adverse effects of superoxide on beta cell glucose sensing are caused by activation of UCP2. Krauss et al. (2003) concluded that superoxide-mediated activation of UCP2 may play an important role in the pathogenesis of beta cell dysfunction and type II diabetes.
Conti et al. (2006) engineered transgenic mice to overexpress Ucp2 in hypocretin neurons (Hcrt-Ucp2) and reported that these mice had elevated hypothalamic temperature. The effects of local temperature elevation on the central thermostat resulted in a 0.3- to 0.5-degree Celsius reduction of the core body temperature. Fed ad libitum, Hcrt-UCP2 transgenic mice had the same caloric intake as their wildtype littermates but had increased energy efficiency and a greater median life span (12% increase in males; 20% increase in females). Thus, Conti et al. (2006) concluded that modest sustained reduction of core body temperature prolonged life span independent of altered diet or calorie restriction.
Emre et al. (2007) showed that streptozotocin (STZ)-induced diabetes was strongly accelerated in Ucp2-knockout mice compared with wildtype mice. STZ-treated Ucp2-knockout mice showed increased intraislet lymphocyte and macrophage infiltration, increased Il1b (147720) and nitric oxide production from macrophages, and increased nitric oxide/ROS-induced damage compared with STZ-treated wildtype mice.
Esterbauer et al. (2001) found an association between obesity (BMIQ4; 607447) and a common G/A polymorphism (rs659366) in the UCP2 promoter region at position -866. The G/G and G/A genotypes were more frequent in the obese group than in the never-obese group.
Bulotta et al. (2005) studied the distribution of the -866G/A UCP2 SNP in 746 type 2 diabetes patients and 327 healthy unrelated Caucasians from Italy. Compared with -866G/G carriers, a progressively reduced (P = 0.01) risk of type 2 diabetes was observed in -866G/A and -866A/A subjects, with the latter showing an approximately 50% risk reduction (OR = 0.51; 95% CI, 0.3-0.8; p = 0.003). Conversely, the -866G/G genotype was associated with increased risk (OR = 1.31; 95% CI, 1.01-1.71). Overall, the population risk attributable to the UCP2 -866G/G genotype was about 12%. Bulotta et al. (2005) also tested for an effect of the P12A variant of the PPARG2 gene (601487.0002) on diabetes risk given by the UCP2 SNP. After stratifying for the PPARG2 polymorphism, the increased risk conferred by the UCP2 G/G genotype was still evident among P12/P12 homozygous subjects (n = 801; OR = 1.38 ; 95% CI, 1.04-1.83), but seemed to disappear among carriers of the A12 allele (n = 137; OR = 0.87; 95% CI, 0.40-1.91).
Andrews, Z. B., Liu, Z.-W., Wallingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschop, M. H., Shanabrough, M., Cline, G., Shulman, G. I., Coppola, A., Gao, X.-B., Horvath, T. L., Diano, S. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454: 846-851, 2008. Note: Erratum: Nature 459: 736 only, 2009. [PubMed: 18668043] [Full Text: https://doi.org/10.1038/nature07181]
Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves-Guerra, M.-C., Goubern, M., Surwit, R., Bouillard, F., Richard, D., Collins, S., Ricquier, D. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genet. 26: 435-439, 2000. [PubMed: 11101840] [Full Text: https://doi.org/10.1038/82565]
Bouchard, C., Perusse, L., Chagnon, Y. C., Warden, C., Ricquier, D. Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum. Molec. Genet. 6: 1887-1889, 1997. [PubMed: 9302267] [Full Text: https://doi.org/10.1093/hmg/6.11.1887]
Brauner, P., Nibbelink, M., Flachs, P., Vitkova, I., Kopecky, P., Mertelikova, I., Janderova, L., Penicaud, L., Casteilla, L., Plavka, R., Kopecky, J. Fast decline of hematopoiesis and uncoupling protein 2 content in human liver after birth: location of the protein in Kupffer cells. Pediat. Res. 49: 440-447, 2001. [PubMed: 11228274] [Full Text: https://doi.org/10.1203/00006450-200103000-00022]
Bulotta, A., Ludovico, O., Coco, A., Di Paola, R., Quattrone, A., Carella, M., Pellegrini, F., Prudente, S., Trischitta, V. The common -866G/A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy. J. Clin. Endocr. Metab. 90: 1176-1180, 2005. [PubMed: 15562023] [Full Text: https://doi.org/10.1210/jc.2004-1072]
Conti, B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M. C., Lucero, J., Brownell, S., Fabre, V., Huitron-Resendiz, S., Henriksen, S., Zorrilla, E. P., de Lecea, L., Bartfai, T. Transgenic mice with a reduced core body temperature have an increased life span. Science 314: 825-828, 2006. [PubMed: 17082459] [Full Text: https://doi.org/10.1126/science.1132191]
Diao, J., Allister, E. M., Koshkin, V., Lee, S. C., Bhattacharjee, A., Tang, C., Giacca, A., Chan, C. B., Wheeler, M. B. UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival. Proc. Nat. Acad. Sci. 105: 12057-12062, 2008. [PubMed: 18701716] [Full Text: https://doi.org/10.1073/pnas.0710434105]
Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., Harper, J. A., Roebuck, S. J., Morrison, A., Pickering, S., Clapham, J. C., Brand, M. D. Superoxide activates mitochondrial uncoupling proteins. Nature 415: 96-99, 2002. [PubMed: 11780125] [Full Text: https://doi.org/10.1038/415096a]
Emre, Y., Hurtaud, C., Karaca, M., Nubel, T., Zavala, F., Ricquier, D. Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proc. Nat. Acad. Sci. 104: 19085-19090, 2007. [PubMed: 18006654] [Full Text: https://doi.org/10.1073/pnas.0709557104]
Enerback, S., Jacobsson, A., Simpson, E. M., Guerra, C., Yamashita, H., Harper, M.-E., Kozak, L. P. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387: 90-93, 1997. [PubMed: 9139827] [Full Text: https://doi.org/10.1038/387090a0]
Esterbauer, H., Schneitler, C., Oberkofler, H., Ebenbichler, C., Paulweber, B., Sandhofer, F., Ladurner, G., Hell, E., Strosberg, A. D., Patsch, J. R., Krempler, F., Patsch, W. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nature Genet. 28: 178-183, 2001. [PubMed: 11381268] [Full Text: https://doi.org/10.1038/88911]
Fleury, C., Neverova, M., Collins, S., Raimbault, S., Champigny, O., Levi-Meyrueis, C., Bouillaud, F., Seldin, M. F., Surwit, R. S., Ricquier, D., Warden, C. H. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15: 269-272, 1997. [PubMed: 9054939] [Full Text: https://doi.org/10.1038/ng0397-269]
Flier, J. S., Lowell, B. B. Obesity research springs a proton leak. Nature Genet. 15: 223-224, 1997. [PubMed: 9054925] [Full Text: https://doi.org/10.1038/ng0397-223]
Krauss, S., Zhang, C.-Y., Scorrano, L., Dalgaard, L. T., St-Pierre, J., Grey, S. T., Lowell, B. B. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J. Clin. Invest. 112: 1831-1842, 2003. [PubMed: 14679178] [Full Text: https://doi.org/10.1172/JCI19774]
Mattiasson, G., Shamloo, M., Gido, G., Mathi, K., Tomasevic, G., Yi, S., Warden, C. H., Castilho, R. F., Melcher, T., Gonzalez-Zulueta, M., Nikolich, K., Wieloch, T. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med. 9: 1062-1068, 2003. [PubMed: 12858170] [Full Text: https://doi.org/10.1038/nm903]
Millet, L., Vidal, H., Andreelli, F., Larrouy, D., Riou, J.-P., Ricquier, D., Laville, M., Langin, D. Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J. Clin. Invest. 100: 2665-2670, 1997. [PubMed: 9389729] [Full Text: https://doi.org/10.1172/JCI119811]
Park, D., Han, C. Z., Elliott, M. R., Kinchen, J. M., Trampont, P. C., Das, S., Collins, S., Lysiak, J. J., Hoehn, K. L., Ravichandran, K. S. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477: 220-224, 2011. [PubMed: 21857682] [Full Text: https://doi.org/10.1038/nature10340]
Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C.-Y., Xu, C., Vianna, C. R., Balthasar, N., Lee, C. E., Elmquist, J. K., Cowley, M. A., Lowell, B. B. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449: 228-232, 2007. [PubMed: 17728716] [Full Text: https://doi.org/10.1038/nature06098]
Pecqueur, C., Cassard-Doulcier, A.-M., Raimbault, S., Miroux, B., Fleury, C., Gelly, C., Bouillaud, F., Ricquier, D. Functional organization of the human uncoupling protein-2 gene and juxtaposition to the uncoupling protein-3 gene. Biochem. Biophys. Res. Commun. 255: 40-46, 1999. [PubMed: 10082652] [Full Text: https://doi.org/10.1006/bbrc.1998.0146]
Sullivan, P. G., Dube, C., Dorenbos, K., Steward, O., Baram, T. Z. Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann. Neurol. 53: 711-717, 2003. [PubMed: 12783416] [Full Text: https://doi.org/10.1002/ana.10543]
Walder, K., Norman, R. A., Hanson, R. L., Schrauwen, P., Neverova, M., Jenkinson, C. P., Easlick, J., Warden, C. H., Pecqueur, C., Raimbault, S., Ricquier, D., Harper, M., Silver, K., Shuldiner, A. R., Solanes, G., Lowell, B. B., Chung, W. K., Leibel, R. L., Pratley, R., Ravussin, E. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. Hum. Molec. Genet. 7: 1431-1435, 1998. [PubMed: 9700198] [Full Text: https://doi.org/10.1093/hmg/7.9.1431]
Wisloff, U., Najjar, S. M., Ellingsen, O., Haram, P. M., Swoap, S., Al-Share, Q., Fernstrom, M., Rezaei, K., Lee, S. J., Koch, L. G., Britton, S. L. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307: 418-420, 2005. [PubMed: 15662013] [Full Text: https://doi.org/10.1126/science.1108177]
Zhang, C.-Y., Baffy, G., Perret, P., Krauss, S., Peroni, O., Grujic, D., Hagen, T., Vidal-Puig, A., Boss, O., Kim, Y.-B., Zheng, X. X., Wheeler, M. B., Shulman, G. I., Chan, C. B., Lowell, B. B. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105: 745-755, 2001. [PubMed: 11440717] [Full Text: https://doi.org/10.1016/s0092-8674(01)00378-6]