Disease relevance of UCP2

• A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans [1].
• Human UCP2 and 3 expressed in Escherichia coli inclusion bodies are solubilized, and by exchange of sarcosyl against digitonin, nucleotide binding as measured with 2'-O-[5-(dimethylamino)naphthalene-1-sulfonyl]-GTP can be restored [2].
• The main conclusion is that variation in the UCP1, UCP2 or UCP3 genes is not associated with major alterations of body gain [3].
• The three uncoupling protein homologue genes UCP1, UCP2, and UCP3 have been investigated for polymorphisms and mutations and their impact on Type II diabetes mellitus, obesity, and body weight gain or BMI [3].
• Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes [4].
• Neuroprotection in the thalamus correlated with a high expression of UCP2, which is neuroprotective in a number of models of neurodegenerative diseases [5].

Psychiatry related information on UCP2

• Analysis of microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa [6].
• We have previously found an increased physical activity but a similar 24-h energy expenditure (EE) in subjects with the val/val-55 UCP2 genotype compared to those with the ala/ala genotype which indicates that the val-55 allele is statistically associated with a higher metabolic efficiency [7].
• The relative liver UCP2 expression of the five major Chinese carps, shows a close relationship with their food habit: benthos and detritus-eating fish (common carp and mud carp) > planktivorious fish (silver carp and bighead carp) > herbivorous fish (grass carp) [8].
• Fasting-induced T3-mediated UCP2 activation resulted in mitochondrial proliferation in NPY/AgRP neurons, an event that was critical for increased excitability of these orexigenic neurons and consequent rebound feeding following food [9].

High impact information on UCP2

• Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity [1].
• We show here 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 [1].
• The pancreatic beta cell : UCP2 and insulin secretion in diabetes [10].
• The first report of UCP2-deficient mice reported that they had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion [11]. However, this has been found to be an artifact of the strain background distribution. Backcrossed animals in three unique strains (A/J, B6 and 129) all show global oxidative stress in various tissues, including pancreatic islets, and signficantly impaired gllucose-stimulated insulin secretion [10]
• Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli [12].
• Subsequent work on UCP2 has been unable to demonstrate any significant role in thermoregulation and body weight.

Chemical compound and disease context of UCP2

• UCP2 message has been shown to be up-regulated in the CNS by stress signals such as kainate administration or ischemia, and overexpression of UCP2 has been reported to be neuroprotective against oxidative stress in vivo and in vitro, although the exact mechanism has not been fully established [13].
• CONCLUSION: Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy [14].
• 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 [15].
• CONCLUSIONS/INTERPRETATION: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians [16].
• RESULTS: UCP2 mRNA and protein levels were 3- to 4-fold higher in adenocarcinomas, and UCP2 mRNA levels showed significant correlation with increased tumor tissue malondialdehyde contents [17].

Biological context of UCP2

• In conclusion, the similar induction of gene expression observed during fasting in lean and obese subjects shows that there is no major alteration of UCP2 and -3 gene regulation in adipose tissue and skeletal muscle of obese subjects [18].
• UCP2 is widely expressed in human tissues, whereas UCP3 expression seems restricted to skeletal muscle, an important site of thermogenesis in humans [18].
• Uncoupling protein-2 and -3 (UCP2 and UCP3) are mitochondrial proteins that show high sequence homology with the brown adipocyte-specific UCP1 [18].
• We found UCP2 and UCP3 mRNA levels to be highly variable and poorly correlated with measures of energy expenditure and with most factors affecting energy balance [19].
• In contrast to UCP1, which is only present in brown adipose tissue, UCP2 has a wide tissue distribution, whereas UCP3 is expressed predominantly in skeletal muscle [20].

Anatomical context of UCP2

• Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue [1].
• It is straightforward to hypothesize that common polymorphisms of UCP1, UCP2 and UCP3 genes lower metabolic rate by a more efficient energy coupling in the mitochondria [3].
• We also investigated whether the thiazolidinedione, troglitazone, stimulates UCP2 and UCP3 mRNA levels to follow up on the observation that this antidiabetic drug increases the levels of expression in cultured [19].
• Although it has been postulated that UCP2 could induce type 2 diabetes as developed from obesity due to up-regulated UCP2 transcription by FAs in pancreatic beta-cells [21], the increase in UCP2 is in obesity is perhaps a consequence of ROS and attempts to diminish it.
• From the three different UCPs identified so far by gene cloning UCP1 is expressed exclusively in brown adipocytes while UCP2 is widely expressed [22].

Associations of UCP2 with chemical compounds

• Activating omega-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3 [23].
• Only nocturnal urinary norepinephrine excretion could explain a significant fraction of the variability in both UCP2 and UCP3 expression in muscle, but not adipose tissue [19].
• Treatment with thyroid hormone increases expression of the UCP2 and UCP3 genes [20].
• Also mean plasma TSH concentrations 20, 30 and 45 min after the TRH injection increased more with overfeeding among UCP2 A55V (P<0.005) and UCP3 Rsa I CC (P=0.017) subjects [24].
• UCP2 mRNA has a ubiquitous distribution in tissue, namely, in skeletal muscle, white and brown adipose tissue, the gastro-intestinal tract, the lung and the spleen [25].

Physical interactions of UCP2

• We have assessed the expression of the mitochondrial ND2 and ND5 (subunits of the nicotinamide adenine dinucleotide dehydrogenase complex) genes and the nuclear UCP2 (uncoupling protein 2) gene in 22 oxyphilic thyroid tumors and matched controls [26].

Regulatory relationships of UCP2

• UCP1 and UCP2 were expressed in cultured retinal capillary cells whereas UCP3 was not [27].
• We show here that the pancreatic transcription factor PAX6 preferentially binds to and more effectively trans activates the variant than the wild-type UCP2 promoter allele in the beta-cell line INS1-E [28].
• Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems [29].

Other interactions of UCP2

• These results confirm the regulation of UCP2 and UCP3 by the same factors CoQ, fatty acids, and nucleotides as UCP1 [2].
• At high levels of glucose, expression of UCP1, UCP2 and MnSOD increased to accommodate ROS production compensatively [27].
• After defining the terms uncoupling, leak, protein-mediated uncoupling, we discuss the assumption that due to their low abundance the novel mitochondrial uncoupling proteins (UCP2 to UCP5) can provide only a mild uncoupling, i.e. can decrease the proton motive force by several mV only [30].
• RESULTS: The MDR analysis showed a significant gene to gene interaction between the Ala55Val polymorphism in the uncoupling protein 2 gene ( UCP2) and the 161C>T polymorphism in the exon 6 of peroxisome proliferator-activated receptor gamma ( PPARgamma) gene [31].
• EXPERIMENTAL DESIGN: UCP2 expression was characterized by real-time polymerase chain reaction and Western blotting using paired human colon adenocarcinoma and peritumoral specimens [17].

Analytical, diagnostic and therapeutic context of UCP2

• UCP2 and -3 mRNA levels were not correlated with body mass index (BMI) in skeletal muscle, but a positive correlation (r = 0.55, P < 0.01, n = 22) was found between UCP2 mRNA level in adipose tissue and BMI [18].
• In this study we have deduced the genomic structure of the human UCP2 gene by PCR and direct sequence analysis [32].
• UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting [33].
• To directly investigate the correlation between UCP2 expression and insulin resistance, UCP2 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from 100 obese subjects who underwent laparoscopic adjustable gastric banding [34].
• On the other hand, studies in animal and cell culture models identified pancreatic beta-cell UCP2 expression as a main determinant of the insulin secretory response to glucose [28].

References