Disease relevance of UCP3

• Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects [1].
• Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3 [1].
• Also [3H]GTP ([3H]ATP) binding to isolated Escherichia coli (Kd, approximately 5 microm) or yeast-expressed UCP2 (Kd, approximately 1.5 microm) or UCP3 exhibited high affinity, similar to UCP1 [2].
• We conclude it is unlikely that variants in the coding region of the UCP3 gene contribute to the pathogenesis of juvenile-onset obesity among Danish Caucasians [3].
• Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes [4].

Psychiatry related information on UCP3

• Analysis of microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa [5].
• In contrast, regular physical activity, which increases fat oxidative capacity, reduces UCP3 content [6].
• However, the individual differences in UCP3 protein content (16-22 degrees C) correlated positively with the differences in 24 h energy expenditure (r=0.86, P<0.05) [7].
• Among 18 male subjects, skeletal muscle UCP3 mRNA expression was significantly higher in the C/T & T/T group compared to the C/C homozygotes (P<0.02) [8].

High impact information on UCP3

• 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 [9].
• UCP2 and UCP3 are recently identified UCP1 homologues [10].
• We examined the effect of a diet-induced increase in uncoupling protein 3 (UCP3) expression on postexercise PCr resynthesis in skeletal muscle [11].
• However, this HF diet-induced increase in UCP3 expression was not associated with any changes in the rate of muscle PCr resynthesis during conditions of maximal flux through oxidative phosphorylation [11].
• Taken together, our findings demonstrate that increasing muscle UCP3 expression does not diminish the rate of PCr resynthesis, allowing us to conclude that the primary role of UCP3 in humans is not uncoupling [11].

Chemical compound and disease context of UCP3

• Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression [12].
• A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians [8].
• During triglyceride infusion, physiological hyperinsulinemia appears to prevent the induction of UCP-3 mRNA levels [13].

Biological context of UCP3

• We have investigated the regulation of UCP2 and UCP3 gene expression in skeletal muscle and adipose tissue from lean and obese humans [14].
• UCP2 is widely expressed in human tissues, whereas UCP3 expression seems restricted to skeletal muscle, an important site of thermogenesis in humans [14].
• Uncoupling protein-2 and -3 (UCP2 and UCP3) are mitochondrial proteins that show high sequence homology with the brown adipocyte-specific UCP1 [14].
• None of the known polymorphisms in UCP3 or its 5' flanking sequence were associated with weight loss or UCP3 mRNA abundance [1].
• In this study we have determined the intron/exon organization of the coding region of the UCP3 gene and performed single strand conformation polymorphism (SSCP) analysis and direct sequencing of variants of the gene in 60 Caucasian subjects with juvenile-onset obesity [3].

Anatomical context of UCP3

• 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 cells [15].
• UCP3 protein levels were increased nearly fivefold in skeletal muscle mitochondria isolated from fasted squirrels compared with nonhibernators, but proton leak kinetics in the presence of BSA were unchanged [16].
• UCP2 and UCP3 mRNA expression in the vastus lateralis was measured by RT-PCR with beta-actin mRNA used as an internal control [17].
• A longer period of exposure to chronic positive energy balance conditions may be necessary before sequence variation in UCP2 and UCP3 makes an impact on thyroid metabolism to influence body mass and composition changes [18].
• Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose [19].

Associations of UCP3 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 [2].
• 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 [15].
• Furthermore, UCP3 gene expression was found to correlate negatively with body mass index and positively with sleeping metabolic rate in Pima Indians [20].
• Treatment with thyroid hormone increases expression of the UCP2 and UCP3 genes [20].
• The association of the UCP2 A55V and UCP3 Rsa I CC genotypes with a greater increase in the TSH response to TRH load could reflect a compensatory mechanism counteracting the effects of overfeeding [18].

Regulatory relationships of UCP3

• UCP1 and UCP2 were expressed in cultured retinal capillary cells whereas UCP3 was not [21].
• IGF-1 treatment prevented the glucose-induced neurite degeneration and UCP3 down-regulation [22].
• In wild-type but not mutant primary brown adipocytes, UCP3 gene expression was stimulated by treatment with peroxisome proliferator activated receptor (PPAR) ligands [23].
• Furthermore, changes in UCP3L mRNA expression and UCP3 protein content induced by the diet were positively correlated with changes in cytosolic fatty acid-binding protein content (r = 0.93, p = 0.023 and r = 0.84, p = 0.039, respectively) [24].
• We conclude that SH-SY5Y cells express UCP3 natively and that the expression is regulated by IGF-I via the IGF-I receptor [25].

Other interactions of UCP3

• Yin yang haplotypes were observed only in PTHR1 and UCP3 [26].
• Slow component of [V]O(2) kinetics: the effect of training status, fibre type, UCP3 mRNA and citrate synthase activity [17].
• Our results suggest that the LEP and UCP2/UCP3 genes are unlikely to have a substantial effect on variation in obesity phenotypes in this particular US Caucasian population [27].
• Direct interaction between UCP3 and 14.3.3 theta could be demonstrated after in vitro translation by coimmunoprecipitation [28].
• Exercise induced a significant (P < 0.05) increase (2- to 3-fold) in transcription of the pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) genes in the reduced glycogen leg only [29].

Analytical, diagnostic and therapeutic context of UCP3

• RESEARCH DESIGN AND METHODS: We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene [4].
• We now report the molecular cloning of a third uncoupling protein homologue, designated UCP3 [30].
• UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting [31].
• Uncoupling protein-3 (UCP3) mRNA expression in reconstituted human muscle after myoblast transplantation in RAG2-/-/gamma c/C5(-) immunodeficient mice [32].
• Muscle biopsies were obtained from the vastus lateralis, from which UCP3 mRNA was quantified by Northern blot, and fiber type was determined by use of the myosin ATPase staining procedure [33].

References