UCP1: The original uncoupling protein - and perhaps the only one? New perspectives on UCP1, UCP2, and UCP3 in the light of the bioenergetics of the UCP1-ablated mice

The availability of a UCP1-ablated mouse has enabled critical studies of the function of UCP1, UCP2, and UCP3. Concerning UCP1, its presence in brown-fat mitochondria is associated with innate uncoupling, high GDP-binding capacity, and GDP-inhibitable Cl- permeability and uncoupling-but the high fatty acid sensitivity found in these mitochondria is observed even in the absence of UCP1. The absence of UCP1 leads to low cold tolerance but not to obesity. UCP1 ablation also leads to an augmented expression of UCP2 and UCP3 in brown adipose tissue, making this tissue probably the one that boasts the highest expression of these UCPs. However, these very high expression levels are not associated with any inherent uncoupling, or with a specific GDP-binding capacity, or with a GDP-sensitive Cl- permeability, or with any effect of GDP on mitochondrial membrane potential, or with an increased basal metabolism of cells, or with the presence of norepinephrine- or fatty acid-induced thermogenesis in cells, and not with a cold-acclimation recruited, norepinephrine-induced thermogenic response in the intact animal. Therefore, it can be discussed whether any uncoupling effect is associated with UCP2 or UCP3 when they are endogenously expressed and, consequently, whether (loss of) uncoupling (thermogenic) effects of UCP2 or UCP3 can be invoked to explain metabolic phenomena, such as obesity.