ArticlePDF AvailableLiterature Review

Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight

Authors:

Abstract and Figures

The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals, such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously lose body fat.International Journal of Obesity advance online publication, 31 July 2012; doi:10.1038/ijo.2012.124.
Content may be subject to copyright.
REVIEW
Adaptive thermogenesis can make a difference in the ability
of obese individuals to lose body weight
A Tremblay
1
, M-M Royer
2
, J-P Chaput
3
and E
´Doucet
4
The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive
diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals,
such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over
the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease
in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also
documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted
decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive
decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese
individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced
thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater
predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in
thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously
lose body fat.
International Journal of Obesity (2013) 37, 759–764; doi:10.1038/ijo.2012.124; published online 31 July 2012
Keywords: appetite; brown adipose tissue; energy expenditure; fat; metabolic rate; weight loss
INTRODUCTION
The study of an adaptive component of energy expenditure is
an issue that has more than a century of age. Indeed, at the
beginning of the last century, it was reported that body weight
stability could be maintained despite substantial variations in
daily energy intake (EI).
1
This was followed by a long series of
investigations that confirmed the body’s potential to adapt its
energy expenditure to attenuate the impact of fluctuations in
energy balance on body energy stores. As reflected by the
epidemic of obesity, the long-term matching of EI to energy
expenditure is not easily achieved for a large proportion of the
population. In light of this, one can assume that the coupling
between EI and energy expenditure goes beyond naive allusions
to the lack of good dietary compliance. One of the culprits that
has also been frequently proposed to be part of the determinants
of obesity is adaptive variations in thermogenesis. Specifically, a
reduced capacity to increase energy expenditure in a context of
overfeeding would result in an increase in body fat accumula-
tion over time. Conversely, a greater-than-predicted decrease in
energy expenditure in response to a negative energy balance
may damper efforts to lose body fat. In recent papers, we reported
the quantitative importance of adaptive thermogenesis for
weight-reduced obese individuals,
1,2
which may in fact be more
important than initially perceived. In the present paper, we pursue
this analysis by documenting some issues that are directly related
to obesity management. These include the contribution of
adaptive thermogenesis to resistance to lose fat, the inability to
reach satiety at energy balance in a weight-reduced obese state
and the long-term persistence of depressed thermogenesis
following weight loss amongst other things.
MATERIALS AND METHODS
As described in the Introduction section, this paper presents a conceptual
extension of the review articles recently published by the authors.
Specifically, its main goal is to integrate recent research developments
that could be translated into clinically relevant questions. Thus, this review
is not the outcome of a systematic literature survey based on key words
and selection criteria. It rather represents a conceptual integration of
papers that are deemed to provide the best answers to the following
questions: (i) What is the clinical meaning of adaptive thermogenesis?
(ii) Why is adaptive thermogenesis occurring? (iii) What is the relationship
between adaptive thermogenesis, resistance to lose fat, appetite control
and rate of weight loss? Globally, the answers to these questions help
discussing the extent to which it is relevant to intervene in reduced-obese
individuals.
Adaptive thermogenesis: what does it mean for the clinician?
Adaptive thermogenesis has been defined as the change in energy expen-
diture following acute and/or long-term overfeeding and underfeeding.
In some studies, it has also been investigated by using catecholamines,
caffeine, ephedrine and adrenergic blockers to induce changes in thermo-
genesis. As previously described,
1
these stimuli were found to induce
statistically significant changes in thermogenesis. However, the quantitative
estimates of adaptive thermogenesis derived from these studies were found
to be of little significance from a clinical perspective.
1
Department of Kinesiology, PEPS, Laval University, Quebec City, Quebec, Canada;
2
Department of Nutrition and Food Science, Laval University, Quebec City, Quebec, Canada;
3
Healthy Active Living and Obesity Research Group, Children’s Hospital, Eastern Ontario Research Institute, Ottawa, Ontario, Canada and
4
School of Human Kinetics, University of
Ottawa, Ottawa, Ontario, Canada. Correspondence: Professor A Tremblay, Department of Kinesiology, PEPS, Laval University, Quebec City, Quebec, Canada G1V 0A6.
E-mail: angelo.tremblay@kin.msp.ulaval.ca
Received 2 December 2011; revised 15 May 2012; accepted 4 July 2012; published online 31 July 2012
International Journal of Obesity (2013) 37, 759– 764
&
2013 Macmillan Publishers Limited All rights reserved 0307-0565/13
www.nature.com/ijo
In our opinion, a significant progress has been achieved in this field by
the group of Leibel et al.
3
who quantified adaptive thermogenesis by
calculating the difference between measured energy expenditure and
a value predicted by variations in fat-free mass and fat mass. These
investigators showed that body weight loss induced a greater than
predicted decrease in resting energy expenditure, which on average
ranged between 250 and 300 kcal per day. Our measurements in obese
individuals subjected to a weight-reducing program provided comparable
estimates.
4,5
We have also shown that this adaptive reduction in
thermogenesis is seemingly present in the active state.
6
Furthermore, we
have emphasized that there are substantial inter-individual response
variations, suggesting that adaptive thermogenesis probably exerts a
much greater influence on fluctuations of energy balance in some
individuals.
2
At the other end of the spectrum, an increase of 760 kJ per
day has been shown to occur after 3 days in overfed subjects. Similar to
energy deprivation, a large range of responses ( 110 to 1610 kJ per day)
was noted,
7
again emphasizing that inter-individual variations might
therefore be important to consider when assessing factors that may limit
weight loss and/or weight gain. For the clinician, the calculation of the
greater-than-predicted decrease in energy expenditure in response to a
weight-loss program provides a useful clinical marker that may reflect the
ability of an obese individual to be a ‘good responder’ to the intervention.
Indeed, as it is difficult to prescribe food intake that imposes an energy
deficit exceeding 700–800 kcal per day to obese individuals, the decrease
in energy expenditure in response to weight loss can entirely compensate
for this prescribed deficit.
1
In this regard, it is also relevant to point out that
aging can affect the response to a weight-loss intervention, as it has been
shown to be associated with a greater-than-predicted decrease in resting
energy expenditure.
8
Adaptive thermogenesis: why is it occurring?
Adaptive thermogenesis may represent a defense mechanism that is set
to protect energy stores from accelerated growth or depletion. The first
explanation that has been proposed to explain thermogenic variations
in animals is related to the activity of brown adipose tissue (BAT).
As described by Rothwell and Stock,
9
BAT activity has sufficient impact
on energy metabolism to explain individual variations in the proneness
to obesity. In animals, this observation has been corroborated by many
investigators, but the demonstration of relevance in humans has generally
failed to provide a substantial quantitative importance of BAT in energy
metabolism. However, interest for this aspect has been recently reactivated
by a series of papers providing evidence of seemingly important amounts
of BAT in human adults and of an impact on energy metabolism that
might be greater than previously considered.
10–12
In this regard, the fact
that glucose uptake by BAT represents an index of its metabolic activity
has prompted the development of new phenotypic characterization.
13,14
Recent progress in position emission tomography scanning has permitted
to obtain BAT imaging by using uptake of 2[
18
F] fluoro-2-dioxy-glucose.
15
For instance, Yoneshiro et al.
16
tested healthy men who underwent
fluorodeoxyglucose positron emission tomography measurements after
2 h of cold exposure. Compared with the measurement in a warm environ-
ment, cold exposure increased energy expenditure to a substantially
different extent between the BAT-positive and -negative groups (410 vs
42 kcal per day). More recently, the demonstration of a specific role of BAT
on thermogenesis in humans was done with even more specificity by
Ouellet et al.
17
who tested healthy men under control cold-exposure
conditions. These investigators showed that cold-induced increase in total
energy expenditure was related to an activation of oxidative metabolism
in BAT but not in adjoining skeletal muscles and subcutaneous adipose
tissue.
Beyond the demonstration of validity of the greater-than-predicted
change in energy expenditure as a measure of adaptive thermogenesis,
3
Rosenbaum et al.
18
have also contributed to identify some metabolic
correlates of this variable. Indeed, a decrease in thermogenesis in weight-
reduced obese individuals was found to be associated with a decrease in
plasma T3 and leptin, as well as sympathetic nervous system activity.
18
They also showed that low-dose leptin administration reverses autonomic
and neuro-endocrine adaptations occurring with weight loss
19
and the
decrease in energy expenditure that normally occurs with weight loss.
20
Our research experience is also concordant with the notion of an impor-
tant role of leptin in variations of adaptive thermogenesis in humans.
Indeed, the decrease in plasma leptin was significantly correlated with the
greater-than-predicted decrease in energy expenditure both at rest and
during exercise in obese individuals having experienced weight loss.
5,6
Another explanation of thermogenic variations in humans pertains
to the environmental interference with metabolic regulation. In this case,
the main problem is related to the impact of some persistent organic
pollutants (POPs), which promote detrimental effects on the control of
energy expenditure as far as maintaining lower levels of adiposity is
concerned. It has been shown that POPs alter the development of the
thyroid gland in animals,
21
promote a decrease in concentrations of
thyroid hormones in animals
22,23
and humans,
24,25
and accentuate their
body clearance.
26,27
Furthermore, POPs have been found to decrease
skeletal muscle oxidative enzymes
28
and inhibit mitochondrial activity.
29,30
We also reported that changes in POP levels with weight loss were the best
predictor of the decrease in resting metabolic rate (RMR) in obese
individuals.
31
Subsequently, we compared the predictability of the greater-
than-predicted decrease in sleeping metabolic rate in response to weight
loss by changes in plasma leptin and POPs.
32
As expected, both variables
significantly predicted the adaptive reduction in thermogenesis, but the
contribution of POP changes was greater than that attributable to leptin
changes.
Available data support a role of heredity on inter-individual variations in
energy expenditure, in conditions of overfeeding or underfeeding leading
to weight loss. To investigate this issue, Bouchard et al.
33
tested monozygotic
twins in whom the within-pair resemblance relative to the between-pair
resemblance in changes in energy expenditure provided an indication of
a genotype–environment interaction effect. In twins tested under short-
term (22 days) and long-term (100 days) conditions of overfeeding and
underfeeding, resting and exercise energy expenditure were measured
under standardized conditions. In general, a significant within-/between-
twin pair variance ratio was observed,
34–38
suggesting a role of heredity in
thermogenic adaptations to a positive or negative energy balance.
The analysis of factors potentially influencing thermogenesis also
imposes to consider some mechanistic explanations that have not been,
up to now, the object of systematic investigation. Among these factors, the
impact of probiotics has been examined by Lee et al.
39
in mice with diet-
induced obesity, which were supplemented with Lactobacillus rhamnosus
TL60, a strain which produces conjugated linoleic acid, over 8 weeks.
Following this treatment, mice showed reduced body weight without any
change in energy expenditure. In humans, this issue does not seem to
have been directly studied. The investigation of this issue would require to
take into account that heat produced by gut bacteria is not measured by
indirect calorimetry, which is ‘blind’ to energy-consuming anaerobic
processes.
40
Dietary calcium is another factor that has been studied for its potential
thermogenic effect. In transgenic mice, which expressed the agouti gene in
adipose tissue under the control of the aP2 promoter, the anti-obesity
effect of dietary calcium and dairy products was confirmed in a series
of studies.
41,42
In addition, high-calcium diets were found to inhibit
lipogenesis, stimulate lipolysis, increase thermogenesis and suppress fat
accretion and weight gain in animals fed isocaloric diets.
41
This is
consistent with human studies that evaluated the effects of high calcium
intake on RMR and thermic effect of a meal. In 11 subjects having partici-
pated in a randomized within-subject meal protocol comparing low to
high calcium intake, diet-induced thermogenesis was significantly increased
by an isoenergetic high-calcium meal.
43
Accordingly, St-Onge et al.
44
reported
an increase in resting energy expenditure after 1 week of milk supple-
mentation compared with a supplementation with sugar-only beverage in
children. However, when studied in the context of a weight-loss program,
calcium supplementation was not found to promote significant changes in
energy expenditure.
45,46
Among other factors that have the potential to influence thermogenesis,
adenovirus-36 seropositivity is relevant, as its association with obesity was
confirmed both in adults
47
and children.
48
However, to our knowledge, no
animal or human studies have directly tested the effects of adenovirus-36
on adaptive thermogenesis. Finally, the impact of short sleep duration is
also worth considering, as its link with the risk of obesity is also well
documented.
49,50
In this regard, sleep deprivation in rats was found to
promote an increase in both EI and energy expenditure. This increase in
energy expenditure seemed to be mediated by an elevation of the
expression of uncoupling proteins (UCP), for example, UCP1 in BAT
51
and
UCP2 in skeletal muscle.
52
Further research will also be useful to determine
if this stimulation of UCPs is the consequence of the sleep-induced
hyperphagia
53
or the stress related to inadequate sleep-related recovery. In
humans subjected to a reduced calorie diet, Nedeltcheva et al.
54
reported
that sleep deprivation induced a decrease in relative fat oxidation.
In summary, there is growing evidence suggesting that both BAT and
white adipose tissues are involved in adaptive thermogenesis, as BAT is
Adaptive thermogenesis and weight loss
A Tremblay et al
760
International Journal of Obesity (2013) 759 – 764 &2013 Macmillan Publishers Limited
metabolically well equipped to produce heat, and that molecules secreted
(for example, leptin) or stored (for example, POPs) by white fat cells also
appear as factors that may have an important role in adaptive thermo-
genesis. It thus seems of interest to investigate the interaction between the
two tissues in the determinism of variations in thermogenesis observed in
humans experiencing fluctuations in energy stores.
Adaptive thermogenesis and weight loss
Adaptive thermogenesis and resistance to lose fat. Although weight
reduction is a difficult task, the maintenance of lost weight seems to
require the deployment of even more efforts.
55
Indeed, the relapse of more
than 80% of individuals to pre-weight-loss levels of body fatness after
otherwise successful weight loss is likely due to the coordinated actions of
metabolic, neuro-endocrine, autonomic and behavioral changes that
oppose the maintenance of a reduced body weight.
56
The occurrence of
an apparent resistance to lose fat (plateau) is often interpreted as being
the result of a lack of dietary and/or physical activity guidelines
compliance. However, the adaptive reduction in thermogenesis can be
sufficiently pronounced in some cases to counteract further weight loss,
even in the compliant patients.
1,2,57
As mentioned earlier, the experiments conducted by Leibel et al.
3
have
significantly contributed to our understanding of the clinical impact of
adaptive thermogenesis by showing that the maintenance of a reduced or
elevated body weight was associated with compensatory changes in
energy expenditure. We confirmed these observations in obese individuals
subjected to a weight-reducing program by showing that the decrease in
energy expenditure substantially exceeded the reduction predicted by
changes in fat-free and fat mass.
6,57
More recently, we substantiated the
clinical relevance of adaptive thermogenesis by reporting the case of a
woman who gained 2 kg of body weight despite her careful compliance
to a 15-week weight-reducing program consisting a supervised diet
(500 kcal per day).
1
This clinical paradox was explained by a decrease
in RMR of 552 kcal per day, thereby supporting the potential of adaptive
thermogenesis in impeding obesity treatment in some individuals.
In an attempt to further understand the extent to which diminished
thermogenesis may contribute to the occurrence of resistance to lose fat,
we designed a sequential therapeutic approach requiring the testing of
obese men at every 5 kg of weight loss and at resistance to fat loss.
According to our previous experience, the weight-loss program was based
on a low-fat diet ( 700 kcal per day) supervised by a dietitian and
performing exercise under the supervision of a kinesiologist. This protocol
induced weight loss in the participants who became resistant to lose fat
after a 12.7-kg (12.4% of initial body weight; 93.8% from fat stores) weight
loss over 8 months.
58
As shown in Figure 1, the adaptive reduction in
thermogenesis reached 706 kJ per day at plateau and represented 30.9%
of the compensation in energy balance that led to resistance to further
lose fat. Thus, even if changes in appetite control and EI occurring with
weight loss remain important determinants of resistance to lose fat in
obese individuals,
4
it is likely that the adaptive reduction in thermogenesis
also represents an important contributor to the inability to further lose
weight over time. Taken together, these studies highlight the fact that
adaptive thermogenesis could be quantitatively more important than what
is generally perceived by health professionals; some obese individuals
display disproportionate changes in energy expenditure when exposed to
conditions of negative energy balance. In turn, this then possibly impedes
body weight loss.
Adaptive thermogenesis and appetite control. The limited ability to
maintain energy balance in a weight-reduced state is the product of our
difficulty in compensating for the weight-loss-induced reduction in total
energy expenditure.
59
The end result, translated into the overwhelming
complexity of preserving long-term weight loss, is a consequence of
compromised appetite control. Indeed, there is accumulating evidence
supporting that the control of food intake is compromised when body
energy reserves are being depleted. Dieting has been shown to trigger
counter-regulatory adaptations, possibly through downregulation (leptin,
PYY and GLP-1) or upregulation (ghrelin) of peptides known to affect
energy balance.
59
Despite a decrease in total energy expenditure in a
weight-reduced state, there is a concomitant increase in the drive to eat,
4
an effect that is also observed early into energy deprivation
60
and that has
been shown to predict weight relapse.
61
Thus, a reduction in energy
expenditure as observed after weight loss is unfortunately not
accompanied by a proportionate decrease in the drive to eat. The
problem of maintaining energy balance after weight loss is then likely to
be one of reducing EI to compensate for a chronic decrease in energy
expenditure, considering that large amounts of exercise are needed to
maintain weight stability after weight loss.
62
We recently reported that changes in appetite sensations are directly
related to the loss of body fat.
63
Indeed, for each kilogram of fat lost and
independent of initial body weight, women subjected to a calorie-restricted
diet experienced an increase in desire to eat of 5.8 mm and a decrease in
fullness of 3.6 mm in their rating on 150 mm visual analog scales. These
results are novel and emphasize the clinical usefulness of visual analog
scales. Whether or not these could be used to identify potential weight
regainers and poor weight-loss responders remains to be determined.
In an attempt to further understand the disruption in the coupling
between EI and energy expenditure during weight loss, we reanalyzed
data of obese subjects tested at every 5 kg of weight loss until the
occurrence of a plateau, as described in the previous section. To document
the ability of our participants to maintain a given energy balance over
time, we divided their ad libitum EI during a buffet-style meal with their
RMR. These rates (EI
buffet
/RMR
kcal/24 h
) can be regarded as an indicator of
their ability to deal with a negative energy balance and thereby their
vulnerability of relapse. On the basis of previously reported studies,
appetite is expected to increase
4,59
and RMR to decrease
3,18
with weight
loss. Thus, the resulting quotient integrating changes in these two
variables is a theoretical increase with weight loss. Surprisingly, phases 1
and 2 resulted in an improvement of this indicator (see Figure 2),
suggesting that our weight-loss program was adequate and well tolerated
by the participants. This can be explained by the functionality of our
prescribed menus, which included many nutritional properties favoring
satiety, as well as by the physical activity component that attenuated the
decrease in fat-free mass and RMR. However, we observed an opposite
trend at weight-loss plateau, that is, the phase associated with a
substantial reduction in adaptive thermogenesis. Clearly, the subjects
were not able to match EI with energy expenditure, and this scenario then
creates optimal biological circumstances for weight regain. Interestingly,
we also observed a significant association between the adaptive reduction
in thermogenesis and the change in hunger (Figure 3). In other words, the
greater the reduction in adaptive thermogenesis during a weight-loss
program, the greater the increase in the drive to eat. This finding then
suggests that it is more difficult for some individuals (that is, those
experiencing an important reduction in adaptive thermogenesis) to be
satiated in a reduced-obese state than for those experiencing no or little
adaptive thermogenesis over the course of a weight-loss program. In
addition, these observations emphasize that bringing weight loss up to a
state of resistance to further lose weight is counterproductive and
promotes ideal conditions for relapse.
Adaptive thermogenesis and the rate of weight loss. One of the most
consistently reproduced observations in the field of obesity research is that
**
*
0
100
200
300
400
500
600
700
800
900
Adaptive reduction in thermogenesis (kJ/day)
Baseline Phase 1 Phase 2 Plateau
Figure 1. Adaptive reduction in thermogenesis at each phase of a
weight-loss program that consisted of a supervised diet and exercise
in obese men. Mean values with their s.e. Phase 1: 5 kg weight loss.
Phase 2: 10 kg weight loss. Plateau: 12.7 kg weight loss (12.4% of
initial body weight). Adaptive reduction in thermogenesis was
defined as the greater-than-predicted decrease in resting metabolic
rate induced by the weight-reducing program. *Significantly different
from phase 1 and plateau (Po0.05). **Significantly different from
phases1and2(Po0.05). Figure adapted from Tremblay and Chaput.
58
Adaptive thermogenesis and weight loss
A Tremblay et al
761
&2013 Macmillan Publishers Limited International Journal of Obesity (2013) 759 – 764
weight loss is accompanied by a decrease of energy expenditure.
5,64
To obtain a more comprehensive overview of the effects of weight loss on
energy expenditure, we recently conducted a systematic review on this
issue.
65
From these analyses, we reported that when all types of weight-
loss interventions are combined, the resulting figure for weight-loss-
induced reduction in resting energy expenditure is 15.4 kcal kg
1
per day.
As can be seen in Figure 4, there are important differences between the
modes of interventions. As the energy deficit, that is, the gap between
energy expenditure and EI, is likely the greatest at the onset of
interventions, we were also interested in comparing short- and long-term
interventions aimed at inducing weight loss. As initially anticipated, the
analysis of a subset of studies for this systematic review revealed that
short-term interventions (o6 weeks) produced a reduction in energy
expenditure that was twice as much (–28 kcal kg
1
per day) than that
observed for the longer-term interventions (46 weeks; 13 kcal kg
1
per day; Figure 5). As such, one could postulate that in some individuals,
a greater energy restriction may not systematically yield the expected
weight loss if it downplays the magnitude of the energy deficit through a
more aggressive response in the depression of energy expenditure.
Together, the results presented throughout this review would thus tend to
suggest that adaptive thermogenesis may impede the rate of body energy
mobilization, but testing this provides a challenge from an experimental
point of view. Indeed, as greater-than-predicted depressions in energy
expenditure have been noted both for the resting
57
and non-resting
3,6
components of energy expenditure, this implies precise measurements of
total, physical activity and resting energy expenditure. It also implies a
good control of the EI measurement throughout the weight-loss trial.
Accordingly, not many studies have been performed to test whether
alterations in energy metabolism could represent a barrier to weight loss in
some individuals. Among these, Miller and Parsonage
66
published the
results of a study in 29 women who claimed that they could not lose
weight. The participants were secluded in a house for 3 weeks, where they
were fed a standard 1500 kcal per day diet. Under these very controlled
conditions, 19 women lost weight, 9 lost no weight and 1 woman actually
gained weight. What is more, energy expenditure was measured on three
occasions during the 3-week period. In the end, the authors concluded
that women with the lowest basal metabolic rate were the ones who did
not lose weight under very well-controlled conditions. These observations
lend credibility to the postulation that adaptations to energy-restricted
diets, under very controlled conditions, may indeed impede weight loss
attempts in some individuals.
Persistence of adaptive thermogenesis over time. Ravussin et al.
67
reported that low rates of energy expenditure was a risk factor for weight
gain. More relevant to this review, is the relationship between low rates
of energy expenditure and the maintenance of a reduced body weight.
Along these lines, it has been shown that individuals who regain the most
weight over a 16-month follow-up are also those in whom the greatest
depression in 24-h energy expenditure is witnessed during the weight-loss
intervention.
61
As such, the magnitude of the decrease in energy
expenditure that occurs as a response to prolonged energy deficits
*
*
*
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Daily relative energy intake (EI / RMR)
Baseline Phase 1 Phase 2 Plateau
Figure 2. Daily relative energy intake at each phase of a weight-loss
program that consisted of a supervised diet and exercise in obese
men. Mean values with their s.e. EI, energy intake (kJ); RMR, resting
metabolic rate (kJ/24 h). Phase 1: 5kg weight loss. Phase 2: 10 kg
weight loss. Plateau: 12.7 kg weight loss (12.4% of initial body
weight). Daily relative energy intake is an indicator that represents
the ability to deal with a negative energy balance. An increase in this
quotient is generally associated with weight regain. *Significantly
different from baseline (Po0.05). Note: the indicator significantly
decreased in phases 1 and 2, and significantly increased in the
plateau phase compared with baseline values.
-30
-20
-10
0
10
20
30
40
50
60
Adaptive reduction in thermogenesis (kJ/day)
Change in hunger (mm)
y = 0.103x – 50.4
r = 0.73
P < 0.05
n = 8
400 500 600 700 800 900 1000
Figure 3. Association between the adaptive reduction in thermo-
genesis at body weight loss plateau and the change in hunger level
over the course of a weight-loss program that consisted of a
supervised diet and exercise in obese men. Change in hunger level:
plateau baseline. Plateau: 12.7 kg weight loss (12.4% of initial body
weight). Adaptive reduction in thermogenesis was defined as the
greater-than-predicted decrease in resting metabolic rate induced
by the weight-reducing program.
-30
-25
-20
-15
-10
-5
0
Kcal/kg weight loss
**
Pharmaco-
logicalDiet Exercise
Diet &
Exercise Surgical
*
Figure 4. Comparison of the mean rate of changes in resting EE
relative to weight loss with different weight loss interventions in all
males and females (n¼2983). * and windicate significant difference
from diet at Po0.05 and Po0.001, respectively.
-40
-35
-30
-25
-20
-15
-10
-5
0ShortLong
Kcal/kg weight loss
Figure 5. Comparison of the effect of time on the mean rate of
changes in resting EE relative to weight loss with long (X6 weeks)
and short (o6 weeks) interventions. Differences were statistically
significant (Po0.001).
Adaptive thermogenesis and weight loss
A Tremblay et al
762
International Journal of Obesity (2013) 759 – 764 &2013 Macmillan Publishers Limited
leading to weight loss seems to be an important determinant of the long-
term success of weight-loss interventions. In fact, greater reductions in
energy expenditure may increase the degree of difficulty to bridge the gap
with a manageable EI, as weight loss also increases appetite,
4
food reward
and palatability of foods
68
as mentioned previously. Then, addressing
whether or not the greater-than-predicted changes in energy expenditure
persist in the weight-reduced state, if somehow individuals manage to
maintain weight stability after weight loss, becomes interesting and
important. The re-analysis of the semi-starvation data from the classic
experiment of Keys et al.
69
provided some of the first evidence that the
depression of energy expenditure persisted at least for a short period after
the end of the 24 weeks of severe energy deprivation.
70
In fact, basal
metabolic rate remained B10% below predicted values after 12 weeks of
refeeding while the subjects had almost entirely recovered their pre-
starvation body weight. Although these data support the existence of a
depression in energy expenditure that persists beyond the energy
restriction, under conditions where individuals are consuming food ad
libitum after weight loss, it may be argued that this effect may be a carry-
over from subjects having been recently semi-starved. Through the meta-
analysis approach, Astrup et al.
71
provided further documentation of the
possible durability of depressed energy expenditure. They compiled results
from 124 formerly obese women who were compared with 121 women
who had never been obese. Results from the analyses showed that resting
energy expenditure was 5.1% lower in the formerly obese subjects after all
appropriate corrections for differences in body mass had been performed.
Unfortunately, little information was provided as to the time at which the
post weight-loss assessment of energy expenditure was performed in the
formerly obese subjects. More recently, the predicted and measured values
of energy expenditure were compared in subjects who had just completed
a weight-loss intervention designed to induce a 10% body weight reduc-
tion or in subjects who managed to maintain a 10% weight reduction for
at least 1 year.
72
It was reported that the difference between predicted
and measured total energy expenditure and non-resting energy expendi-
ture remained similar after 1 year of weight stability at a lowered body
weight as that observed soon after weight loss. Collectively, these results
underline the possibility that the metabolic adaptations that occur in
response to prolonged energy deficit persist in time and that constant
efforts may need to be deployed in the form of increased energy
expenditure from exercise or strict adherence to lowered EI, similar to the
characteristics of successful long-term weight-loss maintainers.
55
Is it relevant to intervene in reduced-obese individuals?
As presented and discussed in this review, the increase in the drive to eat
and the seemingly persistent depression of different components of energy
expenditure after weight loss, may well complicate the maintenance of
energy balance at that point, which is supported by the overwhelming level
of weight relapse. These observations provide an interesting platform for
investigating approaches that may normalize weight-loss-induced effects on
energy balance. Some studies have investigated the potential of exogenous
leptin administration to attenuate the effects of weight loss on appetite
and changes in energy expenditure. In the first of these two studies, it was
reported that administrating recombinant leptin to human subjects after
weight loss partly corrected some of the weight-loss-induced defects in
energy expenditure.
20
Similarly, administration of leptin during weight loss
has also been shown to attenuate the appetite and hunger responses that
normally occur under such circumstances.
73
Finally, results from a recent
functional imagery trial also showed that administration of recombinant
leptin reestablished the brain response to food cues to levels comparable
to pre-weight-loss patterns.
74
Collectively, these results show that changes
in appetite and energy expenditure that occur in response to weight loss
may be partially reversed with exogenous leptin administration. Whether
or not this approach would lead to improved long-term weight stability
after weight loss remains to be determined.
In conclusion, the observations presented and discussed in this paper
indicate that a decrease in thermogenesis may occur in obese individuals
maintaining a supervised diet–exercise program promoting weight loss.
This adaptation explains a substantial decrease in daily energy needs and
is related to changes in appetite sensations promoting compensation
possibly through increased EI. As these thermogenic changes would seem
to persist over time, they likely contribute to body weight regain following
body weight loss. It thus seems important to further investigate adaptive
thermogenesis in humans, be it for the development of relevant
biomarkers or to improve diagnosis about individual determinants of the
predisposition to obesity.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
AT is partly funded by the Canada Research Chair in Environment and Energy
Balance. JPC holds a Junior Research Chair in Healthy Active Living and Obesity
Research. ED is a recipient of a CIHR/Merck-Frosst New Investigator Award, CFI/OIT
New Opportunities Award and of an Early Researcher Award.
REFERENCES
1 Tremblay A, Major GC, Doucet E, Trayhurn P, Astrup A. Role of adaptive
thermogenesis in unsuccessful weight-loss intervention. Future Lipidol 2007;
2: 651–658.
2 Major GC, Doucet E, Trayhurn P, Astrup A, Tremblay A. Clinical significance of
adaptive thermogenesis. Int J Obes (Lond) 2007; 31: 204–212.
3 Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from
altered body weight. N Engl J Med 1995; 332: 621–628.
4 Doucet E, Imbeault P, St-Pierre S, Almeras N, Mauriege P, Richard D et al. Appetite
after weight loss by energy restriction and a low-fat diet-exercise follow-up. Int J
Obes 2000a; 24: 906–914.
5 Doucet St E , Pierre S, Almeras N, Mauriege P, Richard D, Tremblay A. Changes in
energy expenditure and substrate oxidation resulting from weight loss in obese
men and women: is there an important contribution of leptin? J Clin Endocrinol
Metab 2000b; 85: 1550–1556.
6 Doucet E, Imbeault P, St-Pierre S, Almeras N, Mauriege P, Despres JP et al. Greater
than predicted decrease in energy expenditure during exercise after body weight
loss in obese men. Clin Sci (Lond) 2003; 105: 89–95.
7 Wijers SL, Saris WH, van Marken Lichtenbelt WD. Individual thermogenic
responses to mild cold and overfeeding are closely related. J Clin Endocrinol
Metab 2007; 92: 4299–4305.
8 Alfonzo-Gonzalez G, Doucet E, Almeras N, Bouchard C, Tremblay A. Estimation of
daily energy needs with the FAO/WHO/UNU 1985 procedures in adults: com-
parison to whole-body indirect calorimetry measurements. Eur J Clin Nutr 2004;
58: 1125–1131.
9 Rothwell NJ, Stock MJ. A role for brown adipose tissue in diet-induced thermo-
genesis. Nature 1979; 281: 31–35.
10 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM,
Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men.
N Engl J Med 2009; 360: 1500–1508.
11 Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identifi-
cation and importance of brown adipose tissue in adult humans. N Engl J Med
2009; 360: 1509–1517.
12 Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional
brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525.
13 Chernogubova E, Cannon B, Bengtsson T. Norepinephrine increases glucose
transport in brown adipocytes via beta3-adrenoceptors through a cAMP, PKA,
and PI3-kinase-dependent pathway stimulating conventional and novel PKCs.
Endocrinology 2004; 145: 269–280.
14 Marette A, Bukowiecki LJ. Noradrenaline stimulates glucose transport in rat
brown adipocytes by activating thermogenesis. Evidence that fatty acid activa-
tion of mitochondrial respiration enhances glucose transport. Biochem J 1991;
277: 119–124.
15 Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown
adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293:
E444–E452.
16 Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y et al. Brown
adipose tissue, whole-body energy expenditure, and thermogenesis in healthy
adult men. Obesity (Silver Spring) 2011; 19: 13–16.
17 Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F et al. Brown
adipose tissue oxidative metabolism contributes to energy expenditure during
acute cold exposure in humans. J Clin Invest 2012; 122: 545–552.
18 Rosenbaum M, Hirsch J, Murphy E, Leibel RL. Effects of changes in body weight on
carbohydrate metabolism, catecholamine excretion, and thyroid function. Am J
Clin Nutr 2000; 71: 1421–1432.
19 Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S
et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine
adaptations to maintenance of reduced weight. J Clin Invest 2005; 115:
3579–3586.
20 Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose
leptin administration reverses effects of sustained weight-reduction on energy
expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol
Metab 2002; 87: 2391–2394.
Adaptive thermogenesis and weight loss
A Tremblay et al
763
&2013 Macmillan Publishers Limited International Journal of Obesity (2013) 759 – 764
21 Collins Jr. WT , Capen CC, Kasza L, Carter C, Dailey RE. Effect of polychlorinated
biphenyl (PCB) on the thyroid gland of rats. Ultrastructural and biochemical
investigations. Am J Pathol 1977; 89: 119–136.
22 Bastomsky CH. Goitres in rats fed polychlorinated biphenyls. Can J Physiol Phar-
macol 1977; 55: 288–292.
23 Byrne JJ, Carbone JP, Hanson EA. Hypothyroidism and abnormalities in the kinetics
of thyroid hormone metabolism in rats treated chronically with polychlorinated
biphenyl and polybrominated biphenyl. Endocrinology 1987; 121: 520–527.
24 Hagmar L, Rylander L, Dyremark E, Klasson-Wehler E, Erfurth EM. Plasma con-
centrations of persistent organochlorines in relation to thyrotropin and thyroid
hormone levels in women. Int Arch Occup Environ Health 2001; 74: 184–188.
25 Sala M, Sunyer J, Herrero C, To-Figueras J, Grimalt J. Association between serum
concentrations of hexachlorobenzene and polychlorobiphenyls with thyroid
hormone and liver enzymes in a sample of the general population. Occup Environ
Med 2001; 58: 172–177.
26 Van Birgelen AP, Smit EA, Kampen IM, Groeneveld CN, Fase KM, Van der Kolk J
et al. Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism:
use in risk assessment. Eur J Pharmacol 1995; 293: 77–85.
27 Barter RA, Klaassen CD. UDP-glucuronosyltrans ferase inducers reduce thyroid
hormone levels in rats by an extrathyroidal mechanism. Toxicol Appl Pharmacol
1992; 113: 36–42.
28 Imbeault P, Tremblay A, Simoneau JA, Joanisse DR. Weight loss-induced rise in
plasma pollutant is associated with reduced skeletal muscle oxidative capacity.
Am J Physiol Endocrinol Metab 2002; 282: E574–E579.
29 Narasimhan TR, Kim HL, Safe SH. Effects of hydroxylated polychlorinated biphe-
nyls on mouse liver mitochondrial oxidative phosphorylation. J Biochem Toxicol
1991; 6: 229–236.
30 Pardini RS. Polychlorinated biphenyls (PCB): effect on mitochondrial enzyme
systems. Bull Environ Contam Toxicol 1971; 6: 539–545.
31 Pelletier C, Doucet E, Imbeault P, Tremblay A. Associations between weight loss-
induced changes in plasma organochlorine concentrations, serum T(3) con-
centration, and resting metabolic rate. Toxicol Sci 2002; 67: 46–51.
32 Tremblay A, Pelletier C, Doucet E, Imbeault P. Thermogenesis and weight loss in
obese individuals: a primary association with organochlorine pollution. Int J Obes
Relat Metab Disord 2004; 28: 936–939.
33 Bouchard C, Tremblay A, Despres JP, Nadeau A, Lupien PJ, Theriault G et al. The
response to long-term overfeeding in identical twins. N Engl J Med 1990; 322:
1477–1482.
34 Poehlman ET, Despres JP, Marcotte M, Tremblay A, Theriault G, Bouchard C.
Genotype dependency of adaptation in adipose tissue metabolism after short-
term overfeeding. Am J Physiol 1986a; 250: E480–E485.
35 Poehlman ET, Tremblay A, Fontaine E, Despres JP, Nadeau A, Dussault J et al.
Genotype dependency of the thermic effect of a meal and associated hormonal
changes following short-term overfeeding. Metabolism 1986b; 35:3036.
36 Bouchard C, Tremblay A, Despres JP, Theriault G, Nadeau A, Lupien PJ et al. The
response to exercise with constant energy intake in identical twins. Obes Res
1994; 2: 400–410.
37 Tremblay A, Poehlman ET, Nadeau A, Dussault J, Bouchard C. Heredity and
overfeeding-induced changes in submaximal exercise VO2. J Appl Physiol 1987;
62: 539–544.
38 Tremblay A, Poehlman ET, Despres JP, Theriault G, Danforth E, Bouchard C.
Endurance training with constant energy intake in identical twins: changes over
time in energy expenditure and related hormones. Metabolism 1997; 46: 499–503.
39 Lee HY, Park JH, Seok SH, Baek MW, Kim DJ, Lee KE et al. Human originated
bacteria, Lactobacillus rhamnosus PL60, produce conjugated linoleic acid and
show anti-obesity effects in diet-induced obese mice. Biochim Biophys Acta
2006; 1761: 736–744.
40 Gnaiger E. Heat dissipation and energetic efficiency in animal anoxibiosis: econ-
omy contra power. J Exp Zoo 1983; 228: 471–490.
41 Shi H, Dirienzo D, Zemel MB. Effects of dietary calcium on adipocyte lipid
metabolism and body weight regulation in energy-restricted aP2-agouti trans-
genic mice. Faseb J 2001; 15: 291–293.
42 Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary
calcium. Faseb J 2000; 14: 1132–1138.
43 Ping-Delfos WC, Soares M. Diet induced thermogenesis, fat oxidation and food
intake following sequential meals: influence of calcium and vitamin D. Clin Nutr
2011; 30: 376–383.
44 St-Onge MP, Claps N, Heshka S, Heymsfield SB, Kosteli A. Greater resting energy
expenditure and lower respiratory quotient after 1 week of supplementation with
milk relative to supplementation with a sugar-only beverage in children. Meta-
bolism 2007; 56: 1699–1707.
45 Major GC, Alarie FP, Dore J, Tremblay A. Calcium plus vitamin D supp lementation
and fat mass loss in female very low-calcium consumers: potential link with a
calcium-specific appetite control. Br J Nutr 2009; 101: 659–663.
46 Teegarden D, White KM, Lyle RM, Zemel MB, Van Loan MD, Matkovic V et al.
Calcium and dairy product modulation of lipid utilization and energy expenditure.
Obesity (Silver Spring) 2008; 16: 1566–1572.
47 Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB et al. Human
adenovirus-36 is associated with increased body weight and paradoxical reduc-
tion of serum lipids. Int J Obes (Lond) 2005; 29: 281–286.
48 Atkinson RL, Lee I, Shin HJ, He J. Human adenovirus-36 antibody status is asso-
ciated with obesity in children. Int J Pediatr Obes 2010; 5: 157–160.
49 Chaput JP, Despres JP, Bouchard C, Tremblay A. The association between sleep
duration and weight gain in adults: a 6-year prospective study from the Quebec
Family Study. Sleep 2008; 31: 517–523.
50 Chaput JP, Leblanc C, Perusse L, Despres JP, Bouchard C, Tremblay A. Risk factors
for adult overweight and obesity in the Quebec Family Study: have we been
barking up the wrong tree? Obesity (Silver Spring) 2009; 17: 1964–1970.
51 Koban M, Swinson KL. Chronic REM-sleep deprivation of rats elevates metabolic
rate and increases UCP1 gene expression in brown adipose tissue. Am J Physiol
Endocrinol Metab 2005; 289: E68–E74.
52 Cirelli C, Tononi G. Uncoupling proteins and sleep deprivation. Arch Ital Biol 2004;
142: 541–549.
53 Brondel L, Romer MA, Nougues PM, Touyarou P, Davenne D. Acute partial sleep
deprivation increases food intake in healthy men. Am J Clin Nutr 2010; 91: 1550–1559.
54 Nedeltcheva AV, Kilkus JM, Imperial J, Schoeller DA, Penev PD. Insufficient sleep
undermines dietary efforts to reduce adiposity. Ann Intern Med 2010; 153: 435–441.
55 McGuire MT, Wing RR, Klem ML, Seagle HM, Hill JO. Long-term maintenance of
weight loss: do people who lose weight through various weight loss methods use
different behaviors to maintain their weight? Int J Obes 1998; 22: 572–577.
56 Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. Int J Obes (Lond)
2010; 34: S47–S55.
57 Doucet E, St-Pierre S, Alme
´ras N, Despre
´s J-P, Bouchard C, Tremblay A. Evidence
for the existence of adaptive thermogenesis during weight loss. Br J Nutr 2001;
85: 715–723.
58 Tremblay A, Chaput JP. Adaptive reduction in thermogenesis and resistance to
lose fat in obese men. Br J Nutr 2009; 102: 488–492.
59 Doucet E, Cameron J. Appetite control after weight loss: what is the role of
bloodborne peptides? Appl Physiol Nutr Metab 2007; 32: 523–532.
60 Doucet E, Pomerleau M, Harper ME. Fasting and postprandial total ghrelin remain
unchanged after short-term energy restriction. J Clin Endocrinol Metab 2004; 89:
1727–1732.
61 Pasman WJ, Saris WH, Westerterp-Plantenga MS. Predictors of weight main-
tenance. Obes Res 1999; 7: 43–50.
62 McGuire MT, Wing RR, Klem ML, Lang W, Hill JO. What predicts weight regain in a
group of successful weight losers? J Consult Clin Psychol 1999; 67: 177–185.
63 Gilbert JA, Drapeau V, Astrup A, Tremblay A. Relationship between diet-induced
changes in body fat and appetite sensations in women. Appetite 2009; 52:
809–812.
64 Bray GA. Effect of caloric restriction on energy expenditure in obese patients.
Lancet 1969; 2: 397–398.
65 Schwartz A, Doucet E. Relative changes in resting energy expenditure during
weight loss: a systematic review. Obes Rev 2010; 11: 531–547.
66 Miller DS, Parsonage S. Resistance to slimming: adaptation or illusion? Lancet
1975; 1: 773–775.
67 Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WGH et al.
Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl
JMed1988; 318: 467–472.
68 Cameron JD, Goldfield GS, Cyr MJ, Doucet E. The effects of prolonged caloric
restriction leading to weight-loss on food hedonics and reinforcement. Physiol
Behav 2008; 94: 474–480.
69 Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The Biology of Human
Starvation. The University of Minnesota Press: Minneapolis, 1950.
70 Dulloo AG, Jacquet J. Adaptive reduction in basal metabolic rate in response to
food deprivation in humans: a role for feedback signals from fat stores. Am J Clin
Nutr 1998; 68: 599–606.
71 Astrup A, Gotzsche PC, van de Werken K, Ranneries C, Toubro S, Raben A et al.
Meta-analysis of resting metabolic rate in formerly obese subjects. Am J Clin Nutr
1999; 69: 1117–1122.
72 Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of
adaptive thermogenesis in subjects who have maintained a reduced body
weight. Am J Clin Nutr 2008a; 88: 906–912.
73 Westerterp-Plantenga MS, Saris WH, Hukshorn CJ, Campfield LA. Effects of weekly
administration of pegylated recombinant human OB protein on appetite profile
and energy metabolism in obese men. Am J Clin Nutr 2001; 74: 426–434.
74 Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. Leptin reverses weight loss-
induced changes in regional neural activity responses to visual food stimuli. J Clin
Invest 2008b; 118: 2583–2591.
Adaptive thermogenesis and weight loss
A Tremblay et al
764
International Journal of Obesity (2013) 759 – 764 &2013 Macmillan Publishers Limited
... We also found significant effects of O 3 exposure on the expression profile of genes involved in BAT-mediated thermogenesis such as UCP1 and PGC1α. These data are of interest because evidence supports that the decrease in thermogenesis is likely associated with a greater predisposition to body weight gain 65 , which is in accordance with previous data from our group showing a less severe decline diseaseassociated weight loss in TDP-43 A315T mice exposed to O 3 . Indeed, we also found a significant upregulation of GLUT4 mRNA levels in the BAT of TDP-43 A315T mice in responses to O 3 exposure, which is an interesting data as we previously reported plasma glucose levels were highest at the end-stage of disease after O 3 exposure in TDP-43 A315T mice 13 . ...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS), a devastating progressive neurodegenerative disease, has no effective treatment. Recent evidence supports a strong metabolic component in ALS pathogenesis. Indeed, metabolic abnormalities in ALS correlate to disease susceptibility and progression, raising additional therapeutic targets against ALS. Ozone (O3), a natural bioactive molecule, has been shown to elicit beneficial effects to reduce metabolic disturbances and improved motor behavior in TDP-43A315T mice. However, it is fundamental to determine the mechanism through which O3 acts in ALS. To characterize the association between O3 exposure and disease-associated weight loss in ALS, we assessed the mRNA and protein expression profile of molecular pathways with a main role in the regulation of the metabolic homeostasis on the hypothalamus and the brown adipose tissue (BAT) at the disease end-stage, in TDP-43A315T mice compared to age-matched WT littermates. In addition, the impact of O3 exposure on the faecal bacterial community diversity, by Illumina sequencing, and on the neuromuscular junctions (NMJs), by confocal imaging, were analysed. Our findings suggest the effectiveness of O3 exposure to induce metabolic effects in the hypothalamus and BAT of TDP-43A315T mice and could be a new complementary non-pharmacological approach for ALS therapy.
... La perte de poids par réduction de la prise alimentaire est un stress pour le corps et s'accompagne par une baisse des besoin énergétique qui se maintien sur le long terme dans un processus que l'on appelle la « thermogénèse adaptative » [178,179]. L'absence d'expression de la leptine provoque un fort appétit et une sévère obésité chez l'humain comme la souris [168,169,182]. Elle agit en inhibant la production de sérotonine qui favorise l'appétit [183]. ...
Thesis
Le microbiote intestinal est un écosystème de microorganismes dont les nombreuses fonctions digestives et immunitaires le rendent indispensable à la bonne santé de son hôte. Une susceptibilité génétique associée à des perturbations environnementales peut rompre cet équilibre et entrainer une dysbiose. L’inflammation chronique en résultant se traduit en différents troubles locaux et systémiques. Ainsi la dysbiose a été mise en cause dans la physiopathologie des maladies inflammatoires chroniques de l’intestin et également au développement de troubles métaboliques associés à l’obésité.Les peptides antimicrobiens sont des molécules du système immunitaire innée ayant des fonctions de contrôle de la population bactérienne au niveau de la barrière intestinale et empêchant le contact direct entre celles-ci et les cellules épithéliales.L’objectif de cette thèse est d’étudier le potentiel thérapeutique des peptides antimicrobiens dans le traitement de maladies liées à la dysbiose comme les MICI et le syndrome métabolique. Pour cela Lactococcus lactis, une bactérie lactique interagissant de manière transitoire avec la barrière épithéliale intestinale, a été utilisée comme vecteur de la molécule d’intérêt. Durant cette thèse j’ai pu établir que la cathélicidine humaine (hCAP18) et REG3A avaient un impact sur le microbiote et amélioraient les symptômes de la colite induite et de l’obésité chez le rongeur.
... Although the existence of facultative DIT and the role of BAT for DIT remains debated [29,32,44], previous studies showed that facultative DIT was mediated, at least partly, through BAT-mediated thermogenesis [27,45]. Several reports have also shown that DIT can increase EE in response to overfeeding and eventually, retard excessive energy intake and weight gain in rodents [27,[46][47][48]. In adult humans, several studies have indicated that the activation of BAT is involved in the generation of DIT [49][50][51]. ...
Article
Full-text available
Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.
... Similarly, individuals with a limited capacity to increase energy expenditure following overfeeding, originally referred to as 'luxuskonsumption' , have increased susceptibility to weight gain compared with those who have greater increases in energy expenditure with overfeeding [49,71,72]. Consistent with the inverse association between energy expenditure and weight gain susceptibility, individuals with diet-resistant obesity have a greater decrease in energy expenditure while on a low-calorie diet compared to individuals who lose weight quickly [73][74][75]. Diet-induced weight loss can prompt the undesirable loss of FFM [76], exacerbating weight-loss-induced adaptive thermogenesis. Interindividual differences in energy metabolism likely underlie the considerable variability in adaptive thermogenesis that may enhance or perturb weight loss capacity. ...
Article
Full-text available
Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
... While AT after WL has been widely studied and discussed [6], the lack of concordance among methodologies employed to assess AT and/or how REE is predicted was recently highlighted [9]. AT has been studied as a possible barrier especially in WL maintenance, contributing to weight regain [10][11][12]. Moreover, its influence on long-term weight management has been recently questioned, as some authors found that this "phenomenon" seems to be attenuated or even disappeared after a period of weight stabilization [13][14][15][16][17]. Regarding moderate WL, while some studies suggest that a disproportionate decrease in REE appears during WL and may persist during the weight-reduced state [10,18], others have found no evidence of AT in any of the EE components [19,20]. ...
Article
Full-text available
Purpose Despite adaptive thermogenesis (AT) being studied as a barrier to weight loss (WL), few studies assessed AT in the resting energy expenditure (REE) compartment after WL maintenance. The aim of this study was twofold: (1) to understand if AT occurs after a moderate WL and if AT persists after a period of WL maintenance; and (2) if AT is associated with changes in body composition, hormones and energy intake (EI). Methods Ninety-four participants [mean (SD); BMI, 31.1(4.3)kg/m2; 43.0(9.4)y; 34% female] were randomized to intervention (IG, n = 49) or control groups (CG, n = 45). Subjects underwent a 1-year lifestyle intervention, divided in 4 months of an active WL followed by 8 months of WL maintenance. Fat mass (FM) and fat-free mass (FFM) were measured by dual-energy X-ray absorptiometry and REE by indirect calorimetry. Predicted REE (pREE) was estimated through a model using FM, FFM. EI was measured by the “intake-balance” method. Results For the IG, the weight and FM losses were − 4.8 (4.9) and − 11.3 (10.8)%, respectively (p < 0.001). A time–group interaction was found between groups for AT. After WL, the IG showed an AT of -85(29) kcal.d−1 (p < 0.001), and remained significant after 1 year [AT = − 72(31)kcal.d−1, p = 0.031]. Participants with higher degrees of restriction were those with an increased energy conservation (R = − 0.325, p = 0.036 and R = − 0.308, p = 0.047, respectively). No associations were found between diet adherence and AT. Following a sub-analysis in the IG, the group with a higher energy conservation showed a lower WL and fat loss and a higher initial EI. Conclusion AT in REE occurred after a moderate WL and remained significant after WL maintenance. More studies are needed to better clarify the mechanisms underlying the large variability observed in AT and providing an accurate methodological approach to avoid overstatements. Future studies on AT should consider not only changes in FM and FFM but also the FFM composition.
... The findings of this study may also guide future approaches to achieve a healthier body composition following bariatric surgery. Given it is a major determinant of resting metabolic rate, preserving LBM is expected to result in a greater and more durable weight loss, and enhanced health-related quality of life [38][39][40][41][42]. The trajectory of body composition parameters in the present study highlights that LBM depletion occurs predominantly in the first 6 months of weight loss, and most noticeably in the initial month. ...
Article
Full-text available
Background The relationship between weight loss and body composition is undefined after bariatric surgery. The objective of this study was to compare body composition changes in patients with excess weight loss ≥ 50% (EWL ≥ 50) and < 50% at 12 months post-operatively (EWL < 50). Methods A prospective cohort study was completed on patients undergoing bariatric surgery at two tertiary hospitals between 2017 and 2021. Body composition was measured with dual-energy X-ray absorptiometry immediately before surgery, and at 1, 6, and 12 months post-operatively. Body mass index (BMI), fat mass (FM), lean body mass (LBM), and skeletal muscle index (SMI) trajectories were analysed between patients with EWL ≥ 50% and EWL < 50%. Results Thirty-seven patients were included in this series (EWL ≥ 50% n = 25, EWL < 50% n = 12), comprising of both primary and revisional bariatric surgery cases, undergoing a sleeve gastrectomy (62.2%), Roux-en-Y gastric bypass (32.4%), or one anastomosis gastric bypass (5.4%). The EWL ≥ 50% group demonstrated a more optimal mean FM-to-LBM loss ratio than the EWL < 50% group. EWL ≥ 50% patients lost 2.0 kg more FM than EWL < 50% patients for each 1 kg of LBM lost. EWL ≥ 50% was also associated with an increase in mean SMI% over 12 months (5.5 vs. 2.4%; p < 0.0009). Across the whole cohort, the first month after surgery accounted for 67.4% of the total LBM reduction that occurred during the 12-month post-operative period. Conclusion This data suggests EWL ≥ 50% is associated with a more optimal body composition outcome than EWL < 50%. LBM reduction occurs predominantly in the early post-operative period. Graphical abstract
... Compensatory responses in REE during negative energy balance that are independent of changes in FM and FFM (i.e., AT) may attenuate weight loss (4,28,29). Therefore, identifying predictors of metabolic adaptation may contribute to better treatment of obesity and weight management (30). The findings from our study linking sRAGE isoforms and AT were mixed and depended on the mathematical models used to predict AT. ...
Article
Full-text available
Background: Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives: We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods: Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results: Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions: This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.
... This problem is further aggravated by age and a decline in muscular tissue, hepatic insulin resistance, as well as perimuscular inflammation observed with severe obesity (29)(30)(31). Therefore, a compensatory decrease in resting energy expenditure is a major obstacle to successful treatment of obesity, and increasing resting energy expenditure could be a potential solution to obesity and weight cycling (32)(33)(34). ...
Article
Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardio-vascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ('yo-yo effect' or weight cycling). Strategies that increase REE are an attractive treatment option. Brown fat tissue engages in non-shivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g. 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (Chimeric Antigen Receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacologic mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.
Article
Full-text available
Background Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss. Methods From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention. Findings Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training. Interpretation Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes. Funding Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS), a devastating progressive neurodegenerative disease, has no effective treatment. Recent evidence supports a strong metabolic component in ALS pathogenesis, raising additional therapeutic targets against ALS. At this respect, improvements in motor de cits and disease-associated weight loss after repeated exposures to ozone (O 3) in the mouse model of ALS based on TDP-43 proteinopathy (TDP-43 A315T mice) have been reported. Here, the underlying molecular mechanisms to determine whether O 3 exposure induces metabolic changes in ALS have been investigated. Molecular biology analysis demonstrated that O 3 signi cantly modi ed the expression pro le of hypothalamic neuropeptides, altering phosphorylation levels of the signal transducer and activator transcription 3 (STAT3) and protein kinase B (Akt), concomitantly to increase the expression of genes involved in metabolism and thermogenesis in the brown adipose tissue (BAT) of TDP-43 A315T mice. Composition of fecal gut microbiome of exposed TDP-43 A315T mice varied signi cantly compared to wild type (WT) controls. Densitometric analysis of neuromuscular junction, indicated that O 3 does not impaired the progression of disease in the skeletal muscle. Our ndings suggest the effectiveness of O 3 exposure to induce metabolic effects in the hypothalamus and BAT of this ALS mouse model and may be a new complementary non-pharmacological approach for ALS therapy.
Article
Background: Results of leptin administration in mice, rats, and humans provide a rationale for therapeutic augmentation of circulating leptin (OB protein) concentrations in obese humans; this may reduce food intake, increase metabolic rate, and lower body mass. Objective: We assessed the effects of weekly subcutaneous pegylated polyethylene glycol (PEG)-OB protein administration on appetite and energy metabolism in obese men. Design: We performed a randomized, double-blind, placebo-controlled trial in 30 obese men [body mass index (in kg/m²): 34.2 ± 3.6; age: 44.7 ± 7 y]. Subjects received 20 mg PEG-OB protein/wk for 12 wk while limiting their energy intake to 2.1 MJ/d. Results: During treatment, appetite and hunger before breakfast decreased and remained lower in the PEG-OB-protein group, whereas they increased and remained higher in the placebo group (P < 0.0001). During treatment, hunger decreased in the PEG-OB-protein group (P < 0.05) and cognitive restraint increased in the placebo group (P < 0.0001). Neither appetite nor food intake changed significantly during the ad libitum evening meal. Under energy balance conditions in the respiration chamber, appetite at the end of treatment was not significantly different from baseline despite similar, significant reductions in 24-h energy intake, energy expenditure, sleeping metabolic rate, body mass, fat mass, and fat-free mass (P < 0.01 for all) in both groups. Conclusion: Treatment with PEG-OB protein modified subjective appetite at a dosage that produced no changes in body composition, energy expenditure, or body mass loss relative to placebo treatment, suggesting that PEG-OB protein has central rather than peripheral biological activity in obese men.
Article
Reports an error in the original article by M. T. McGuire et al ( Journal of Consulting and Clinical Psychology , 1999[Apr], 67[2], 177–185). On page 181, the Figure 1 caption was incorrect. The correct caption is provided. (The following abstract of this article originally appeared in record 1999-10771-002 .) This study identified predictors of weight gain versus continued maintenance among individuals already successful at long-term weight loss. Weight, behavior, and psychological information was collected on entry into the study and 1 year later. Thirty-five percent gained weight over the year of follow-up, and 59% maintained their weight losses. Risk factors for weight regain included more recent weight losses (less than 2 years vs. 2 years or more), larger weight losses (greater than 30% of maximum weight vs. less than 30%), and higher levels of depression, dietary disinhibition, and binge eating levels at entry into the registry. Over the year of follow-up, gainers reported greater decreases in energy expenditure and greater increases in percentage of calories from fat. Gainers also reported greater decreases in restraint and increases in hunger, dietary disinhibition, and binge eating. … (PsycINFO Database Record (c) 2016 APA, all rights reserved)
Article
Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
Article
Objectives—Hexachlorobenzene (HCB) is a highly lipophilic organochlorine compound of widespread environmental occurrence, that accumulates in the biological system. It aVects the porphyrine metabolism, thyroid hormones, and the liver function in animals. Although HCB is one of the most common organochlorine compound in humans, little investigation on its health eVects has been done. Polychlorobiphenyls (PCBs) are also widespread toxic environmental contaminants. The aim of the present study was to investigate the association of serum HCB and PCB concentrations with thyroid hormone status and liver enzymes in human. Methods—Thyroid stimulating hormone (TSH), total and free thyroxine (T4), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and a-glutamyltransferase (GGT) were measured as biological markers of thyroid and liver function in a rural population sample older than 14 years (n=192, except for TSH with n=608) highly exposed to HCB. Serum concentrations of HCB were measured by gas chromatography coupled to electron capture detection. Results—After adjustment for confounding variables, there was a significant negative association between serum HCB concentrations and total T4 (a decrease of 0.32 µg/dl per each unit, ln ng/ml, of increase of HCB) and a positive association with GGT (a relative increase of 10 % per each ln unit of increase of HCB), although most subjects (92%) were within the normal range for both T4 and GGT. These associations were not modified after adjustment for total lipid content or for other organochlorine compounds. The association of T4 and GGT with PCB was smaller although significant. No association was found with the other biochemical markers. Conclusions—These results suggest that the internal dose of HCB of this population may reflect a subtle metabolic eVect on thyroid function and an enzymatic induction activity. Further studies are needed to evaluate the health impact of these eVects in more susceptible populations, such as infants. (Occup Environ Med 2001;58:172‐177)