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obesity reviews
Obesity Management
Recent advances in adaptive thermogenesis: potential
implications for the treatment of obesity
S. L. J. Wijers, W. H. M. Saris and W. D. van Marken Lichtenbelt Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Large inter-individual differences in cold-induced (non-shivering) and diet- induced adaptive thermogenesis exist in animals and humans. These differences in energy expenditure can have a large impact on long-term energy balance and thusbody weight (when other factors remain stable). Therefore, the level of adaptive Received 16 July 2008; revised 21 September thermogenesis might relate to the susceptibility to obesity; efforts to increase adaptive thermogenesis might be used to treat obesity. In small mammals, themain process involved is mitochondrial uncoupling in brown adipose tissue Address for correspondence: Sander Wijers, (BAT), which is regulated by the sympathetic nervous system. For a long time, it was assumed that mitochondrial uncoupling is not a major physiological con- tributor to adaptive thermogenesis in adult humans. However, several studies conducted in recent years suggest that mitochondrial uncoupling in BAT and skeletal muscle tissue in adult humans can be physiologically significant. Othermechanisms besides mitochondrial uncoupling that might be involved are futilecalcium cycling, protein turnover and substrate cycling. In conjunction with recentadvances on signal transduction studies, this knowledge makes manipulation ofadaptive thermogenesis a more realistic option and thus a pharmacologicallyinteresting target to treat obesity.
Keywords: Calcium cycling, mitochondrial uncoupling, protein turnover,
substrate cycling.
obesity reviews (2009) 10, 218–226
(2). Recently, it has been shown that the individual Background
The fast growing prevalence of overweight and obesity and overfeeding are related (3). Therefore, cold- and in our society progressively affects public health. Obesity diet-induced adaptive thermogenesis is likely to share raises the risk of developing high blood pressure, diabetes the same regulatory mechanism. Therefore, it is feasi- type II and arteriosclerosis, all of which are risk factors ble to aim more research at metabolic reactions to cold for cardiovascular diseases. The problem of obesity has given a strong impulse towards metabolic studies. Small Adaptive thermogenesis in response to cold exposure differences in energy expenditure might have large long- can be divided in two types: shivering thermogenesis (ST) term effects on body weight (1). One of the suggested and non-shivering thermogenesis (NST). The underlying metabolic factors involved in the development of obesity mechanisms of NST and diet-induced adaptive thermogen- is adaptive thermogenesis. It is defined as the regulated esis are not fully elucidated yet. In this review we focus on production of heat in response to environmental tempera- ture or diet. It protects the organism from cold exposure First, we discuss the metabolic responses after cold expo- and regulates energy balance (EB) after changes in diet sure and overfeeding and its respective neuronal regulation.
Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
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Recent advances in adaptive thermogenesis Thereafter, we describe the most likely potential mecha- sure to 15°C showed a significant increase in energy expen- diture of 0.86 MJ d-1 (winter) and 0.57 MJ d-1 (summer),while the absence of shivering was confirmed by elec-tromyogram measurements (15). The significant increase in metabolic rate in winter compared with summer conditions Back in the 1950s, it was already shown in rodents that showed a cold acclimatization effect in the subjects.
oxygen consumption increased two- to fourfold after cold Considerable inter-individual differences in the metabolic exposure (4). During daily cold exposure, shivering gradu- response existed (-0.23 to 2.15 MJ d-1), which remained ally decreased towards zero intensity in 20 d, while no throughout the seasons. Subjects that hardly increased decrease in oxygen consumption was found (5,6). This their energy expenditure during summer were also low indicates the existence of NST. A few years later, similar responders during winter and vice versa.
results were found in man. During winter, when subjects The above underlines that the metabolic response to cold were acclimatized to lower temperatures, energy expendi- exposure is an individual trait. A diminished energy expen- ture increased about 25% upon cold exposure. After 10 d of diture is associated with an increase in body mass, while cold exposure, shivering faded away, but energy expenditure other factors remain fixed. Thus, low responders to cold remained elevated to the same level (7). This increase in might have a higher risk to gain weight than the subjects energy expenditure during cold exposure without shivering that have the ability to increase their energy expenditure, can be considered to be the first proof of NST in humans.
given an equal eating pattern. Claessens-van Ooijen et al. The observed smaller amount of NST upon cold exposure (16) recently showed that short-time mild-cold exposure in adult humans (compared with rodents) might be caused (60 min at 15°C) resulted in a smaller increase in energy by the larger surface to volume ratio. Therefore, relatively expenditure in obese subjects compared with lean subjects less heat loss occurs with comparable core temperatures of (6.4% vs. 17.2%). Keith et al. (17) proposed a possible approximately 37°C. Human newborns are able to increase relation between the recent increase in the prevalence of their energy expenditure more than twofold without shiver- obesity and the fact that people nowadays live in a ther- ing (8), an increase comparable to that in rodents.
moneutral zone more often and, therefore, do not need to Most studies on cold exposure in humans are carried out expend extra energy to achieve thermal comfort.
in severe cold, when shivering also occurs (9,10). In these The most well-known mechanism to protect an organism circumstances it is hard to make a distinction between ST against cold exposure is shivering. It can elicit increases in and NST, as ST is superimposed over NST. However, before oxygen consumption up to five times basal metabolic rate shivering starts, NST can be observed. During pre-shivering (BMR) (18). Upon activation of the primary motor centre (room temperature of 15°C), resting metabolic rate for shivering of the posterior hypothalamus, muscle fibres increased by 12% (range -6% to 28%) (11). Also, attenu- are starting to contract involuntarily (19). As no work is ation of NST using medications has been performed.
performed, heat is produced. However, as muscle fatigue Administering propranolol, a non-selective b-adrenergic occurs after longer periods of shivering, this is not an receptor blocker decreased oxygen consumption after cold acclimatization mechanism for cold exposure but a protec- exposure (room temperature of 5°C) with 26%, whereas tive mechanism to protect the organism from acute cold there were no differences in shivering intensity (12). As exposure. Therefore, shivering is not covered further in this propranolol inhibits the NST response (see chapter regula- tion), the decrease in energy expenditure is comparable tothe amount of NST in the non-blocked status. In conclu- sion, these studies showed evidence for the existence ofNST in adult humans.
After overfeeding, the same amount of excess energy intake In 1980, the same phenomenon has been described in does not invoke the same body weight gain in all people humans after mild-cold exposure (22 vs. 28°C), without (20–25) (Table 1). In a classical study, Bouchard et al. (20) shivering. A mean increase in energy expenditure of 7% showed that overfeeding induced a weight gain of 4.3– (range 2% to 12%) was observed (13). Recently, some 13.3 kg after an excess energy intake of 353 MJ in 100 d.
other studies of mild-cold exposure in human subjects This implies a threefold range in energy cost of weight gain have been performed. After mild-cold exposure of 60 h, the total daily energy expenditure (TDEE) increased with An important aspect in these studies is the level of com- 0.8 MJ d-1. As no shivering was registered, the full meta- pliance, as is discussed extensively in the British Journal of bolic response could be explained by NST (14). In this Nutrition after publication of the paper by Lammert et al. study, the range in inter-individual variation of the increase (23). Most of the studies mentioned above (20,21,23–25) in energy expenditure was large, 0.15–1.45 MJ d-1. In a maximized compliance by supervision during meals. Vom- comparable setting in the same lab, short-term (3 h) expo- iting could be the only way to surpass the supervision; it is 2008 The Authors
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Table 1 Weight gain ranges in a selection of overfeeding studies
*High fat feeding.
†High protein feeding.
EB, energy balance.
not likely that all non-gainers in these studies did mislead ences were large, ranging from -0.11 to 1.61 MJ d-1 (3).
supervisors and vomited. Furthermore, an underestimation These differences in energy expenditure may correspond to of baseline energy requirements could be involved. The the large inter-individual differences in weight gain after studies measuring baseline energy expenditure (21,24,25) ensured adequate weight maintenance energy intake levels, Reduction of adaptive thermogenesis can also be inter- while studies assessing baseline energy requirements with preted as a defensive, body mass saving, mechanism after questionnaires might have underestimated both baseline underfeeding, as reviewed by Major et al. (27). Although and overfeeding energy requirements (20,22,23). As both over 80% of the variation in energy expenditure is categories of estimation for baseline energy expenditure explained by fat free mass, in several underfeeding studies give similar ranges of cost of weight gain, no effect of the (28–30) energy expenditure decreased below the expected estimation method on weight gain is expected.
value. In this case, adaptive thermogenesis prevents sub- As energy intake was standardized in the studies men- tioned above, the differences in weight gain have to becaused by a difference in diet-induced thermogenesis (DIT), the increase in energy expenditure in response to foodintake. DIT can be divided into two categories: obligatory Animal studies revealed that cold exposure, detected and facultative thermogenesis. The obligatory part of DIT peripherally, is integrated by the hypothalamus, which acti- consists of all processes related to the digestion, absorption vates the efferent pathways of the sympathetic nervous and processing of food. The facultative component enables system (SNS). The SNS innervates (among others) ther- ‘wasting’ of energy after a high caloric meal and prevents the mogenic targets as the brown adipose tissue (BAT) and storage of energy. The inter-individual differences in weight skeletal muscle (2). Several studies have shown that rodents gain can be explained by the variability in potency of this with a blocked SNS or lacking catecholamines cannot facultative component. Stock’s (26) reanalysis of several maintain body temperature during cold exposure (31,32).
studies showed even larger inter-individual differences after Also, administration of b-adrenergic receptor agonists diets unbalanced in protein content. The larger cost of caused an increase in energy expenditure (50–150% weight gain in these unbalanced diets presumably protects increase, dependent on cold acclimation), comparable to for deficiencies in underrepresented essential proteins. When the reaction to cold (31). Furthermore, storage of calories there are deficiencies for a certain protein, more energy is during normal caloric intake is increased after blocking the expended, in order to be able to consume more, thus also more proteins, without too much weight gain.
In humans, comparable results have been found. Infusion The link between energy expenditure and weight gain of noradrenaline and adrenaline caused similar metabolic after overfeeding in humans has been shown by Levine reactions as mild-cold exposure (24%–36% increase et al. (24). In an out-patient study giving 4.2 MJ of excess in BMR) (34). The sympathetic control of adaptive energy per day for 8 weeks, the increase in TDEE (on thermogenesis is mediated by b1- and b2-adrenoceptors, average 2.28 MJ d-1) correlated negatively to the gain in fat while energy expenditure is not affected by a1- and mass (r = -0.77). Recently, a mean increase of 0.76 MJ d-1 a2-adrenoceptors (35). The role of b3-adrenoceptors in was shown after 3 d of 60% overfeeding in the confined energy expenditure regulation, except in BAT, is not clear space of a respiration chamber. The inter-individual differ- yet (36). Propranolol administration (a non-selective Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
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Recent advances in adaptive thermogenesis b-adrenergic blocker) after glucose infusion induced a (e.g. glycogen) (45) will reveal more information (46). In decrease in glucose-induced energy expenditure from 2.3 to combination with cold exposure tests or b-agonist admin- 1.7 MJ d-1 (37), which is comparable with the reaction to istration, relative contributions of tissues for adaptive ther- Postulated mechanism behind
adaptive thermogenesis
Skeletal muscle is potentially one of the largest contributorsto adaptive thermogenesis in humans. An adrenaline Most reactions in energy metabolism are tightly regulated.
infusion, which caused an increase of 25% in whole body An amount of fuel gives stoichiometric amounts of NADH energy expenditure, stimulated the forearm muscle to and FADH2. Fixed amounts of protons are pumped out consume 90% more oxygen. Extrapolated to the whole of the mitochondrial matrix per molecule of NADH and body, skeletal muscle would account for about 40% of FADH2 (10 and 6 respectively). ATP synthase needs three adrenaline-induced thermogenesis (38). Controversially, protons to convert ADP and Pi to ATP. Finally, fixed noradrenaline infusion did not increase muscle blood flow amounts of ATP are used for cellular work (47). However, and decreased the arteriovenous oxygen concentration dif- efficiency of these processes is not 100%, and energy is ference over the muscle (39). However, the authors stated, dissipated under normal baseline conditions (i.e. heat pro- in their discussion, that the muscle blood flow measuring duction). To enable an increase in thermogenesis following technique they used had the tendency to underestimate cold exposure without shivering, the efficiency of these blood flow, which might have affected their results greatly.
processes has to be changed. Eligible processes for this Furthermore, local concentrations of noradrenaline might energy dissipation are mitochondrial uncoupling, futile not be large enough to provoke the thermogenic effect.
calcium cycling, protein turnover and substrate cycling. All Results from ingestion of ephedrine, which is a sym- pathomimetic compound acting both centrally and periph-erally, are in line with the abovementioned adrenaline study. Ephedrine ingestion resulted in an average increasein leg oxygen consumption of 25%. This accounted for an The most frequently studied mechanism is mitochondrial extrapolated contribution of the skeletal muscle tissue in uncoupling in BAT, as it accounts for a major portion of ephedrine-induced thermogenesis of 50% (40). Finally, it thermogenesis after cold exposure in rodents (48). This has been shown that carbohydrates induced an increased uncoupling process is executed by uncoupling protein adrenaline concentration, resulting in increased muscle (UCP)-1, a unique inner-membrane protein for BAT. UCP-1 thermogenesis (41). In conclusion, skeletal muscle tissue causes a reflux of protons into the mitochondrial matrix, can be considered to be responsible for a large part of bypassing the ATP synthase. Instead of using the energy stored in the proton gradient to produce ATP, which is the The BAT is the main contributor to adaptive thermogen- energy intermediate in the organism, heat is dissipated esis in small mammals. Its relevance in adult humans has because of this so called proton leakage (48–50). UCP-1 long been questioned. Despite the studies in the eighties knockout mice indeed cannot maintain body temperature showing a lack of a significant contribution of BAT (40), nowadays increasing evidence is found for a significant role Until recently, BAT was commonly thought to be scarcely of BAT in adult humans (42). Until now, no studies have present in adult humans, in spite of studies indicating BAT been carried out quantifying the contribution of BAT to in adult, cold acclimatized humans (52,53). In the 1980s, Astrup et al. (40) performed an elegant study in which they Other tissues, such as the liver, which is highly metabolic first examined the presence of BAT in human necropsies.
active, might also contribute to adaptive thermogenesis in BAT was most abundant in the perirenal region (92% of humans (2), although its contribution has not been quan- specimens contained brown adipocytes); smaller amounts were found in the cervical area (40%) and the pericardial To gain more insight in tissues responsible for the fat depot (20%). They estimated the total content of BAT increase in energy expenditure in adaptive thermogenesis, it to be about 700 g. After stimulating thermogenesis with is necessary to perform more rigorous tests. Combinations ephedrine in man, the authors showed in the same publi- of measuring arteriovenous differences of oxygen or stable cation that the perirenal BAT was not as active as the rat isotopes across tissues (43), micro-dialysis trials measuring BAT. Their calculations revealed that the 700 g of BAT metabolite concentrations in interstitial fluids of the tissues could only account for 14% of the total increase in energy (44) and nuclear magnetic resonance spectroscopy (NMR) expenditure. Nevertheless, only one BAT depot was inves- studies measuring selected substances with 31P, 1H, or 13C tigated, assuming that all depots have the same activity.
2008 The Authors
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Similar results have been found by Cunningham et al. (54) protein content was positively correlated to energy expen- by measuring BAT activity in isolated mitochondria from diture in humans. However, after 60 h of mild-cold expo- the same BAT depot. Following these studies, the attention sure no increase in UCP-3 protein content could be found.
for BAT in adult humans has been decreased.
UCP-3 mRNA was even down-regulated which would con- However, several recent studies (55–57) that were sequently lower the UCP-3 protein content (77). Alterna- tive roles suggested for UCP-3 are not the regulation of energy metabolism but the handling of fatty acids in the CT) showed active BAT-like depots when human subjects mitochondria to prevent lipid-induced oxidative mitochon- were exposed to cold (42). As no FDG-PET/CT measure- drial damage (78,79) and the reduction of the proton gra- ments have been made with concomitantly taken BAT dient to prevent production of reactive oxygen species (80).
biopsies, it has not been shown directly that the active UCP-4 and -5 (or BMCP-1) are brain-specific (81,82) and tissue identified as BAT-like depot is real UCP-1 containing have putative roles in the prevention of neuronal damage BAT. However, the CT images revealed that the active sites (83). Although expression of UCP-4 and UCP-5 was are made up of adipose tissue, and several separate studies increased after cold exposure (84), they are not expected have shown UCP-1 containing BAT cells at active sites to play a role in adaptive thermogenesis as they are not (42,58–61). With a combination of cold exposure, indirect expressed in peripheral tissues thought to be quantitatively calorimetry and FDG-PET/CT, the importance of these important for adaptive thermogenesis (skeletal muscle, BAT-like depots for adaptive thermogenesis can potentially be quantified in vivo on whole body level, rather than at Although the working mechanisms of mitochondrial discrete locations using necropsy studies.
uncoupling in skeletal muscle tissue are not yet fully under- Recently, it has been shown that PRDM16, a protein stood, this does not imply that it is not a factor influencing abundant in BAT, is necessary for the activity of this ther- adaptive thermogenesis. In a high resolution respirometry mogenic tissue (62). Transgenic expression of this gene in study, performed with permeabilized human skeletal white fat precursors stimulated formation of brown fat muscle biopsies, it has been shown that during mild-cold cells, with UCP-1 expression and an increased uncoupled exposure, state 4 (ATP synthase blocking by oligomycin) respiration (62). PRDM16 inhibits the formation of white respiration, i.e. mitochondrial uncoupling, correlated adipose tissue and promotes the formation of BAT by significantly to the increase in energy expenditure (85).
binding to C-terminal-binding protein-1 and -2 and PPAR- Changes in mitochondrial uncoupling in human skeletal g-coactivator-1a and -1b (63). Therefore, it is likely that muscle tissue have been shown before after endurance BAT can be recruited (even in adult humans) and can be a training (86) and triiodothyronine administration (87).
quantitatively important factor for adaptive thermogenesis.
In conclusion, both UCP-1 mediated uncoupling in BAT Testing for the abundance of this protein in (white) adipose and non-UCP-1 mediated uncoupling in skeletal muscle are tissue in human subjects can improve the insight in the candidate working mechanisms for adaptive thermogenesis.
presence in BAT. Surprisingly, PRDM16 has been shown tocontrol a switch between brown fat and skeletal muscle cells (64), indicating that BAT is more similar to skeletalmuscle tissue than to white adipose tissue (65). Expression Some fish living in cold environments (e.g. marlin and tuna) of PRDM16 in myoblasts induced differentiation into have an organ functioning specifically to dissipate heat.
brown adipocytes. UCP-1 containing BAT has been shown This organ warms muscle, viscera, brain and eyes (88). This interspersed between muscle bundles of mice (66). In organ does not have any UCP, as in BAT (89). The heater humans, brown adipocyte progenitors and UCP-1 mRNA organ in fish is a derivative of muscle tissue and contains have been identified in skeletal muscle tissue (67).
an extensive sarcoplasmic reticulum (SR) and T-tubule In humans four homologues of UCP-1 have been found network. It lacks the contractile elements of the muscle that are abundant in other tissues than BAT. UCP-2 and tissue. SR calcium release channels, controlled by Ryano- -3 are more than 50% identical to UCP-1 (68,69) and do dine receptors (Ryr), cause a flow of Ca2+ out of the SR, possess proton transport activity (68,70–73). UCP-2 is triggered by acetylcholine receptors. The balance in abundant in several tissues: spleen, lung, stomach and calcium concentrations has to be corrected by an ATP- white adipose tissue (74). Therefore, it might be playing driven calcium pumping mechanism (Serca-1, sarco/ a role in adaptive thermogenesis, although the effect endoplasmic reticulum Ca2+-ATPase) (89). As Serca-1 uses is expected to be small (75). Also UCP-2 was not up- ATP, which is not used for performing work, energy is regulated during mild-cold exposure, its predominant dissipated in this futile cycle. The same mechanism has role is probably protection from reactive oxygen species been found in humans suffering of malignant hyperther- (76). UCP-3 is an interesting target for research as it is mia. Ryr-1 of these patients is more sensitive to several predominantely expressed in skeletal muscle tissue. UCP-3 anaesthetic agents, leading to an outflow of Ca2+ out of the Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
obesity reviews
Recent advances in adaptive thermogenesis SR, resulting in an compensatory ATP-driven influx, which animals that substrate cycling between de novo lipogenesis produces excessive heat (90). In obese mice, it has been and lipid oxidation is stimulated by leptin, causing an demonstrated that calcium cycling can be triggered with a increase in energy expenditure (101,102). It has also been selective CB1 (cannabinoid receptor 1) antagonist, with shown in humans that mild-cold exposure increased fatty as a result increased energy expenditure and, consequently, acid cycling (103). Upon starvation, it has been shown in weight loss (91). Cold exposure in UCP-1 deficient mice an animal model that fatty acid cycling decreased, regu- showed an increase in Serca-2a expression, which enabled lated by SCD1 (104). Therefore, it is feasible that fatty a calcium cycling induced rise in energy expenditure (92).
acid cycling does contribute to adaptive thermogenesis In rats, underfeeding resulted in a decrease in calcium in humans. Several other substrate cycles exist, like the cycling (compared with an EB condition), implicating that glucose/glycogen cycle, although they are not covered in this inhibition served as an energy saving mechanism (93).
this review, they may also affect adaptive thermogenesis.
Although no human data are available, calcium cycling isone of the eligible mechanisms for adaptive thermogenesisin humans.
Conclusions
Several mechanisms have the potential to contribute to adaptive thermogenesis in man. First, mitochondrial Protein turnover is defined as degradation of proteins into uncoupling in brown adipose fat tissue could be impor- amino acids and resynthesis of new proteins. It is respon- tant, as increasing evidence arises that brown fat cells are sible for a large part of the energy expenditure in an organ- present in adult humans and can be activated by cold ism, 15–20% of BMR (94). Most tissues do exhibit protein exposure. Second, it has been shown that mitochondrial turnover, specifically the skeletal muscle tissue (25% of uncoupling plays a metabolic significant role in skeletal total protein turnover), liver (24%), skin (18%) and small muscle tissue. This can be due to mitochondrial uncou- intestine (15%) (94). Although the skeletal muscle has a pling in muscle fibres, to the possible switch of muscle slower protein turnover than the small intestine, it is still tissue into brown fat or to another mechanism not eluci- the major contributor because of its large tissue mass. As dated yet. Furthermore, fatty acid cycling is also a prom- skeletal muscle and liver possess the largest adaptive ther- ising target for future research, as it has been shown that mogenesis capacity in humans, protein turnover could be a it is increased by cold exposure in humans. As an increase contributor to this process. However, studies in rats (95,96) in calcium cycling after cold exposure has not been mea- and calves (97) did not find any increase in protein turnover sured in humans yet, it is still elusive if it has any influence upon cold exposure. After short-time cold exposure, pro- in humans. Protein turnover is not found to be altered tein synthesis even decreased. It is postulated that this is a during cold exposure, although it increases during over- mechanism for the organism to decrease lean body mass feeding, with large inter-individual differences. Therefore, and herewith, BMR, to save energy under these harsh this process could be of importance in diet-induced adap- On the other hand, it has been shown in humans after Although these mechanisms are potential contributors to carbohydrate overfeeding that protein turnover increased adaptive thermogenesis, more research is needed to quan- by 12% (98). As inter-individual differences were large tify their influence. Arteriovenous concentration difference, (5–25% increase in protein turnover), part of the differ- micro-dialysis and NMR studies in combination with cold ences in adaptive thermogenesis might be explained by this exposure tests could reveal more tissues of interest and mechanism. Therefore, protein turnover might be quanti- their relative contribution. Mitochondrial uncoupling in tatively important, although no data is available on energy BAT can be investigated further with cold exposure tests in combination with PET/CT and PRDM16 measurements.
Human mild-cold exposure tests measuring energy expen-diture in combination with pharmacologically blocking or stimulating processes like calcium cycling, fatty acid cycling Substrate cycling with fatty acids has been observed in and protein turnover will give more insight in the relative patients after severe burn injury (99). In these patients, contribution of these processes for adaptive thermogenesis.
energy expenditure increased largely because of fatty acid Furthermore, long-term cold acclimation tests could reveal cycling, next to the increase in protein turnover. In whether uncoupling capacity can be increased. When more triglyceride-fatty acid cycling, fatty acids are released knowledge has been achieved, these mechanisms can be during lipolysis and subsequently re-esterified rather than used for new strategies to prevent obesity, as they are all oxidized (100). For both reactions different enzymes and capable of increasing energy expenditure and, therefore, ATP are used in a futile way. Recently it was discovered in controlling long-term EB and body weight.
2008 The Authors
Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
Recent advances in adaptive thermogenesis obesity reviews
18. Eyolfson DA, Tikuisis P, Xu X, Weseen G, Giesbrecht GG.
Conflict of Interest Statement
Measurement and prediction of peak shivering intensity in No conflict of interest was declared.
humans. Eur J Appl Physiol 2001; 84: 100–106.
19. Guyton AC, Hall JE. Textbook of Medical Physiology, 11th
edn. Elsevier: Philadelphia, PA, 2006.
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