MOLECULAR STUDIES OF THE UNCOUPLING PROTEIN

The uncoupling protein (UCP) is a proton/anion transporter found in the inner mitochondrial membrane of brown adipocyte. Although UCP has not been detected in mitochondria from any other tissue, it shares structural and catalytic properties with several other mitochondrial carrier proteins. Although UCP was discovered only recently it is one of the most extensively studied mitochondrial carrier proteins. Many tools useful in research on UCP have been developed such as antibodies and cDNAs corresponding to UCP of several animal species. More recently, the mouse, rat, and human genes encoding for UCP have been isolated and sequenced. The availability of these various tools has led to several significant observations. UCP gene expression is strongly controlled at the level of transcription by signals that are activated after the stimulation of brown adipocytes by norepinephrine. The comparison of UCP gene with the genes encoding the adenine nucleotide translocator revealed the existence of structural and evolutionary homologies. Moreover, in humans the UCP gene and one form of adenine nucleotide translocator gene are located on the same chromosome. Recently, the expression of functional UCP in various heterologous systems was achieved (Xenopus oocytes, CHO cells, yeasts). These data will facilitate studies of the structure/function relationship in UCP (identification of residues involved in H+ transport, Cl- transport, nucleotide binding, mitochondrial targeting...). Another aspect of the present research on UCP is the understanding of mechanisms that control the UCP gene and the differentiated commitment of adipose precursor cells to thermogenic brown adipocytes. The multifaceted aspects of research on UCP make this protein interesting in areas of research as different as studies of ion translocating mechanisms, cellular specificity of gene transcription, control of gene expression by neuromediators, adipocyte differentiation, and the pharmacological treatment of obesity.