The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents

Uncoupling protein-3 (UCP3), a mitochondrial membrane transporter, is a can didate effector of thermogenesis, Even though mice with targeted disruption of the UCP3 gene are not obese, indirect evidence suggests that this prote in contributes to the control of energy expenditure in humans, We therefore characterized the human UCP3 gene and compared it with its rodent homologu es with respect to tissue-specific expression and regulatory regions, Like rodent UCP3, human UCP3 was expressed in skeletal muscle and brown adipose tissue (BAT). The short mRNA isoform, UCP3(S), which is absent in rodents, was relatively more abundant in human skeletal muscle in comparison to huma n BAT. Two tissue-specific transcription start sites for each skeletal musc le and BAT were delineated for human UCP3. Tissue-specific transcript initi ation was maintained in both tissues and cultured-cells over a wide range o f expression levels. In contrast, rodent transcripts were initiated at the same site in BAT and muscle tissue, Comparison of human and rodent promoter s indicated a rapid phylogenetic evolution suggesting functional diversific ation. The transcription from tissue-specific promoters in humans is a nove l finding that may provide the basis for therapeutic interventions aimed at regulating energy expenditure in a tissue-specific fashion.