Original Article

Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus

Correspondence to: Wolfgang Patsch.

Uncoupling protein-1 (UCP-1) activity in brown adipose tissue increases thermogenesis, contributes to facultative energy expenditure in humans, and has been implicated in the pathogenesis of rodent obesity. To determine genetic factors controlling UCP-1 expression in humans, we measured intra- and extraperitoneal UCP-1 mRNA abundance levels by a competitive RT-PCR method and compared expression levels with common sequence variations in the ß3-adrenergic receptor gene and the distal UCP-1 gene promoter in obese human subjects. While median and average UCP-1 mRNA levels in both the intra- and extraperitoneal tissue were lower in subjects heterozygous for the Trp64Arg mutation in the ß3-adrenergic receptor gene, this difference was not statistically significant. However, a strong association of intraperitoneal UCP-1 mRNA abundance with the UCP-1 gene polymorphism at -3826 relative to the transcription start site was observed that explained 19.3% of the interindividual variability. The minor allele imparted a dose-dependent reduction on UCP gene expression. The importance of sequence variations at the UCP-1 gene locus as a common source of UCP-1 mRNA abundance variability was supported by allele-specific expression studies utilizing a newly identified polymorphism in exon 2 of the UCP-1 gene that predicts a substitution of alanine by threonine. In four subjects heterozygous for the -3826 polymorphism, the mRNA species transcribed from the wild-type allele accounted for 63 ± 6% percent of total intraperitoneal mRNA abundance. In one subject homozygous for the minor promoter allele, wild-type mRNA was also more abundant than variant mRNA.

Thus, the UCP-1 polymorphism at -3826 is probably only a marker for a frequent mutation causing reduced mRNA expression.—Esterbauer, H., H. Oberkofler, Y-M. Liu, D. Breban, E. Hell, F. Krempler, and W. Patsch. Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus. J. Lipid Res. 1998. 39: 834–844.

Supplementary key words: uncoupling proteins, mRNA, obesity, ß3-adrenergic receptor, RT-PCR

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