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

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 associated thermogenesis (non-exercise activity thermogenesis (NEAT) or ‘fidgeting’ thermogenesis), and those associated with exercise. The thermogenesis associated with exercise is highly variable, and during vigorous physical activity it can be well over 6-fold that associated with the basal metabolic rate. In this issue of The Journal of Physiology, Riley et al. (2016) experimentally address questions regarding the thermogenic functions of UCP3 at the whole body/integrative level. Their experiments dissect the role of UCP3 in facultative, pharmacological and pathological thermogenesis, which they induce in mice, respectively, with environmental cold, the sympathomimetic street-drug methamphetamine, and the bacterial endotoxin lipopolysaccharide. Previous work in these authors’ laboratories established that pharmacological hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’) is absent in mice lacking UCP3 (Mills et al. 2004). The latter phenotype was marked, and has been one of the clearest phenotypic characteristics of UCP3 knockout (KO) mice. Here Riley et al. employ the above physiological, pharmacological and pathological agonists/interventions in a number of mouse models to delineate differences in UCP1 and UCP3 thermogenic functions. That UCP3KO mice have a completely abrogated thermogenic response to lipopolysaccharide response is particularly intriguing. Moreover, the response in UCP1 KO mice is increased compared to wild-type mice; perhaps this is related to interdependence mechanisms of UCP1 expression in BAT and UCP3 expression in skeletal muscle, though the latter was not tested here. Their major results are summarized in Table 1. Altogether these findings support the conclusion that UCP3 can indeed function as an inducible thermogenin, but it is possible that the mechanisms are indirect, and involve ATP turnover mechanisms, beyond non-ATPase/uncoupling types of mechanisms. The mitochondrial anion carrier protein family, of which the UCPs and ANT are members, sometimes translocate more than one molecular species, and it is as yet unknown if UCP3 has such promiscuous characteristics. Moreover, recent findings show that UCP1 and UCP3 are controlled post-translationally through redox mechanisms including sulfenylation and glutathionylation, respectively. The findings of Riley et al., predominantly those associated with the thermogenic responses to ‘drugs and bugs’, are novel and improve our integrative understanding of thermogenesis and of the roles of the uncoupling proteins. None declared.

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