Uncoupling proteins 2 and 3 and their potential role in human obesity

The recently cloned uncoupling proteins 2 and 3 (UCP2, UCP3) cDNAs encode f or proteins with 57-59% homology with brown adipose tissue uncoupling prote in (UCP1). As this latter, the novel UCPs can reduce the proton motive forc e across the inner membrane of the mitochondria, but whether or not they fu nction as uncouplers under physiological conditions has not been unequivoca lly confirmed. Low resting energy expenditure and difficulty oxidizing fat are potential risk factors for the development of obesity, and they could p otentially be affected by the novel UCPs. However, studies largely focused on gene expression regulation do not support a role for the level of expres sion of these proteins in determining energy balance. Overall, the informat ion available suggests more complexity than anticipated and many of the obs ervations are hard to reconcile with a simple role for these proteins in en ergy dissipation. The possibility that these proteins, particularly the ubi quitous UCP2, have unsuspected functions, some of them cell-specific, remai ns open. One such function could be the reduction of the formation of react ive oxygen species during mitochondrial respiration. It is necessary to def ine the physiological role of these proteins in the cell and how their acti vity is regulated. Only when this information is available will we be in a position to determine whether they could be the targets for pharmacological intervention in the treatment or prevention of obesity, and perhaps to inf luence other metabolic processes. (C) 2000 Wiley-Liss, Inc.