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

The recently cloned uncoupling proteins 2 and 3 (UCP2, UCP3) cDNAs encode for proteins with 57–59% homology with brown adipose tissue uncoupling protein (UCP1). As this latter, the novel UCPs can reduce the proton motive force across the inner membrane of the mitochondria, but whether or not they function as uncouplers under physiological conditions has not been unequivocally confirmed. Low resting energy expenditure and difficulty oxidizing fat are potential risk factors for the development of obesity, and they could potentially be affected by the novel UCPs. However, studies largely focused on gene expression regulation do not support a role for the level of expression of these proteins in determining energy balance. Overall, the information available suggests more complexity than anticipated and many of the observations are hard to reconcile with a simple role for these proteins in energy dissipation. The possibility that these proteins, particularly the ubiquitous UCP2, have unsuspected functions, some of them cell‐specific, remains open. One such function could be the reduction of the formation of reactive oxygen species during mitochondrial respiration. It is necessary to define the physiological role of these proteins in the cell and how their activity 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 influence other metabolic processes. Drug Dev. Res. 51:112–123, 2000. © 2000 Wiley‐Liss, Inc.