The aim of this study was to assess in an integrative manner the physiological regulation of uncoupling protein 2 (UCP2) in gilthead sea bream. A contig of 1,325 nucleotides in length with an open reading frame of 307 amino acids was recognized as UCP2 after searches in our transcriptome reference database ( http://www.nutrigroup-iats.org/seabreamdb ). Gene expression mapping by quantitative real-time PCR revealed a ubiquitous profile that clearly differs from that of UCP1 and UCP3 variants with the greatest abundance in liver and white skeletal muscle, respectively. The greatest abundance of UCP2 transcripts was found in the heart, with a relatively high expression level in blood cells, where UCP1 and UCP3 transcripts were practically undetectable. Functional studies revealed that UCP2 mRNA expression remains either unaltered or up-regulated upon feed restriction in glycolytic (white skeletal muscle) and highly oxidative muscle tissues (heart and red skeletal muscle), respectively. In contrast, exposure to hypoxic conditions (18-19% oxygen saturation) markedly down-regulated the UCP2 mRNA expression in blood cells in a cellular environment with increased haematocrit, blood haemoglobin content, and circulating levels of glucose and lactate, and total plasma antioxidant activity. These findings demonstrated that UCP2 expression is highly regulated at the transcriptional level, arising this UCP variant as an important piece of the complex trade-off between metabolic and redox sensors. This feature would avoid the activation of futile cycles of energy wastage if changes in tissue oxidative and antioxidant metabolic capabilities are able to maintain the production of reactive oxygen species at a low regulated level.