Sites and mechanisms of adaptive thermogenesis

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In rodents, a major site of adaptive thermogenesis is brown adipose tissue (BAT). The main mechanism behind BAT thermogenesis relies on the activity of uncoupling protein 1 (UCP1), a mitochondrial inner membrane protein that is uniquely and abundantly expressed in brown adipocytes, which are mitochondria-rich cells (reviewed in references 3-5). When active, UCP1 leaks protons across the mitochondrial inner membrane, allowing dissipation of the proton electrochemical gradient generated by the respiratory chain during fuel oxidation. In this way, the energy that had been stored in the proton gradient is released as heat instead of protons being channeled through the ATP synthase and the energy used in ATP synthesis (Fig. 4.1). Together with the expression of UCP1, a low expression of ATP synthase and a high expression of fatty acid oxidation enzymes and respiratory chain components make brown adipocytes well equipped for inefficient substrate (mainly fat) oxidation. Even in BAT, however, UCP1-independent thermogenic mechanisms are likely to exist, because whereas transgenic mice with toxigene-mediated reduction of BAT are cold sensitive and obese,6 UCP1-deficient (knockout) mice are sensitive to cold exposure but are not obese or especially prone to diet-induced obesity.7

In humans, as in rodents, energy expenditure increases in response to cold exposure and after feeding. The latter phenomenon, which accounts for approximately 10% of total daily energy expenditure, is referred to as the thermic effect of food and comprises two conceptually different

Adaptive Thermogenesis

Heat production

Fig. 4.1 Functioning of the UCP1 in BAT mitochondria. UCP1 dissipates the proton gradient generated by the respiratory chain during nutrient oxidation, leading to the release of energy as heat; Pi, inorganic phosphate (Modified from reference 3).

ATP synthesis

Heat production

Fig. 4.1 Functioning of the UCP1 in BAT mitochondria. UCP1 dissipates the proton gradient generated by the respiratory chain during nutrient oxidation, leading to the release of energy as heat; Pi, inorganic phosphate (Modified from reference 3).

components: the obligatory cost of nutrient utilization (digestion, absorption, processing and storage) and an adaptive component linked to oropha-ryngeal stimulation that typically constitutes 30-40% of the thermic effect of food and is under the control of the sympathetic nervous system (SNS) (see reference 8). The sites and mechanisms of adaptive thermogenesis in humans are unclear. Unlike rodents, adult humans do not have large, well-defined BAT depots, but both rodents and humans have varying numbers of brown adipocytes dispersed within white adipose tissue (WAT) depots, which can be recruited under appropriate stimulation (see reference 9). Skeletal muscle, which represents up to 40% of total body weight and is endowed with significant mitochondrial capacity, may be an important contributor to adaptive thermogenesis; in fact, it has been shown that a significant portion of the variation in metabolic rate between humans can be accounted for by differences in skeletal muscle energy expenditure at rest.10 Other tissues, such as liver and WAT, may also contribute to adaptive thermogenesis.

Apart from UCP1 activity, other mechanisms of adaptive thermogene-sis are poorly understood. One possibility is the activity of mitochondrial uncoupling proteins other than UCP1. In fact, UCP1 homologues with a wider tissue distribution, such as UCP2 and UCP3, have been identified both in rodents and humans (reviewed in references 11-13). UCP2 is expressed in most tissues at varying levels and UCP3 is expressed predominantly in skeletal muscle and BAT. Several studies have shown that these UCP1 homologues have proton transport activity, and a strong linkage between markers in the vicinity of human UCP2 and UCP3 genes (which are adjacent genes in both the human and rat genome) and resting metabolic rate was reported. However, the expression of UCP2 and UCP3 increases with starvation,11,13,14 a state associated with decreased energy expenditure, and neither UCP2-15 nor UCP3-1617 deficient (knockout) mice are obese or especially sensitive to developing diet-induced obesity. Thus, a primary function of the UCP homologues in regulating whole-body energy expenditure seems unlikely.

Adaptive thermogenesis in mammalian tissues may also depend on mechanisms connected to increased utilization of ATP, rather than to uncoupling. Enhanced operation of the so-called 'futile cycles', which imply ATP consumption not linked to the performance of net biological work, may be one of such mechanisms. Examples of potentially important futile cycles include the synthesis and degradation of proteins, the pumping and leakage of ions across membranes, and the esterification and lipolysis of fatty acid/triacylgycerol.18 Increased non-exercise activity thermogenesis (associated with fidgeting, maintenance of posture and other physical activities of daily life) may be another mechanism of adaptive thermogenesis, also based on increased ATP utilization. There are physiological studies in humans suggesting that non-exercise activity thermogenesis is modulated with changes in energy balance, so that it increases with overfeeding and decreases with underfeeding, although the mechanisms behind this regulation are unknown.19

Thermogenesis and substrate oxidation are tightly linked processes. Substrate oxidation drives thermogenesis and thermogenesis favors further substrate oxidation to meet cellular ATP demands. Remarkably in this context, there is increasing evidence that the uncoupling activity of the UCPs may serve primarily to assist oxidative metabolism, and particularly fat oxidation, by facilitating fatty acid handling by mitochondria2^23 and reducing reactive oxygen species (ROS) production in mitochondria.1516 Facilitation of oxidative metabolism at the expense of a small loss of energy could have been the main ancestral role of the UCPs. The molecular basis for a role of the UCPs in mitochondrial fatty acid handling is the capacity of UCPs to uncouple respiration acting as fatty acid cyclers, rather than as proton transporters;24 their role in reducing ROS is related to the fact that the higher the coupling of respiration, the higher the ROS production in the mitochondria.25 The connection of the UCPs with both thermogenesis and oxidative metabolism makes these proteins an interesting target for up-regulation in the context of weight-management strategies.

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