REGULATION OF THE UNCOUPLING PROTEIN GENE-EXPRESSION

Uncoupling protein (UCP) is essential to the thermogenic function of b rown adipose tissue (BAT). The thermogenic role of this protein is due to its capacity to uncouple oxidative phosphorylation in a regulated manner. The thermogenic potential of BAT is determined by its content of UCP. The gene encoding this protein is under complex regulation. Ca techolamines, via cAMP thyroid hormone and retinoic acid, directly sti mulate the gene acting upon an upstream (-2.28/-2.49 kb) enhancer sequ ence, but cAMP may act upon other sequences of the gene as well. CCAAT enhancer binding proteins and peroxisome proliferation activator rece ptor (PPAR)gamma 2 have also been implicated in the regulation of the gene acting on discrete sequences. While the thyroid hormone response and retinoic acid response elements (TRE and RARE) have been well defi ned, the cAMP response elements (CRE) remain elusive. The two TREs are 27 bp apart between -2.33 kb and -2.39 kb. The synergism between cAMP and thyroid hormone seems to reside in a 39 bp sequence downstream (- 2.28/-2.32 kb). The most important CRE, the RARE, a cell-specific enha ncer and a putative PPAR element are all concentrated in a 90 bp regul atory element of great complexity (-2.40/-2.49 kb). Other hormones, su ch as insulin and glucocorticoids, and IGF-I also modulate the express ion of the gene but their effects seem to be largely indirect. Underst anding the regulation of the UCP gene expression may facilitate the de velopment of interventions in obesity and related disorders.