Uncoupling protein-2 (UCP2): Molecular and genetic studies

Thermogenesis is associated to oxygen consumption and cellular respiration. This process is coupled to adenosine-diphosphate (ADP) phosphorylation thr ough the existence of a proton gradient across the inner mitochondrial memb rane. It was postulated that proton leaks through this membrane would uncou ple respiration from adenosine-triphosphate (ATP) synthesis and induce ener gy dissipation as heat. Such a mechanism was identified in thermogenic brow n adipose tissue mitochondria which contain a unique proton carrier referre d to as uncoupling protein (UCP). This UCP is activated by fatty acids and its synthesis is positively controlled by retinoids, thyroid hormones, cate cholamines and rexinoids. In fact, in most types of cells, respiring mitoch ondria release heat and the coupling of substrate oxidation to ADP phosphor ylation is under 100%. It suggested that the partial coupling of respiratio n to ADP phosphorylation was due to proton leaks possibly related to the br own fat UCP. This approach led to the identification of UCP2 and UCP3, two homologues of the brown fat UCP (renamed UCP1). UCP2 gene is widely express ed in tissues and cell types, whereas the UCP3 gene is dominantly expressed in skeletal muscles (and brown fat in mice). Recent genetic, biochemical a nd physiological studies suggest that these novel UCP2 contribute to restin g metabolic rate, fat oxidation and may represent new targets for anti-obes ity compounds.