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 obesity reviews
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 Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
Recent advances in adaptive thermogenesis
obesity reviews 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 obesity reviews
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 Journal compilation 2008 International Association for the Study of Obesity. obesity reviews 10, 218–226
Recent advances in adaptive thermogenesis
obesity reviews
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
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