Drugs and bugs: turning on the heat through UCP1 and UCP3

Abstract

The recent resurgence of biomedical interest in non-shivering thermogenesis has been fuelled by key discoveries, including the following: there is active brown adipose tissue (BAT) in adult humans; brown adipocytes and skeletal muscle cells have common cellular origins; and uncoupling protein-1 (UCP1)-expressing beige adipocytes emerge in white adipose tissue depots following stimulation, for example, by chronic cold exposure, exercise, or peroxisome proliferator-activated receptor-γ (PPARγ) agonists. While there has never been any question of the importance of UCP1 in thermogenesis, a role in this realm for UCP3 has not been clearly demonstrated. UCP1-deficient mice are cold-intolerant (Enerbäck et al. 1997), and develop obesity if housed at thermoneutrality (Feldmann et al. 2009). Shortly after the initial characterizations of the UCP1 knockout mouse, the UCP3 knockout mouse was produced and characterized. Given that UCP3 is expressed in brown adipose and skeletal muscle, it was anticipated that the UCP3 knockout mouse would have a number of physiological and metabolic deficiencies. Surprisingly the whole-body phenotypic characteristics unveiled were minimal, even though there was lower mitochondrial proton leak and increased oxidative stress in skeletal muscle. However, additional metabolic studies of UCP3 in vivo and in vitro revealed its roles in facilitating fatty acid oxidation and minimizing reactive oxygen species (ROS) emission (e.g. Bezaire et al. 2005), and indicated that UCP3 functions in a negative feedback loop in mitochondrial ROS emission (Echtay et al. 2003; Mailloux et al. 2011). Important in the interpretation of these findings is that UCP1 is expressed at exceptionally high levels ( 10% of mitochondrial protein) in BAT, a tissue that is ideally ‘poised’, both biochemically and anatomically, for thermoregulatory thermogenesis. In contrast, UCP3 is expressed at much lower levels in BAT and skeletal muscle, compared to UCP1 in BAT. Physiological thermogenic processes can be categorized as either obligatory or facultative. Obligatory forms are associated with the basal thermogenic processes occurring when the animal is resting in a post-absorptive and thermoneutral state. The latter comprise an animal’s basal metabolic rate. Another form of obligatory thermogenesis is the thermic effect of food. Facultative forms of thermogenesis are those associated with additional energy demanding functions (i.e. beyond the obligatory), and include shivering and non-shivering thermogenesis, non-exercise