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Metabolic Adaptation to Weight Loss: a Brief Review
Preprint · June 2020
DOI: 10.13140/RG.2.2.21486.02887
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Metabolic Adaptation to Weight Loss: a Brief Review
Mario García Martínez-Gómez
Abstract: As the scientific literature has continuously shown, weight loss attempts don`t always
follow a linear fashion nor always go as expected even when the intervention is calculated with
precise tools. One of the main reasons why this tends to happen relies on our body’s biological
drive to regain the weight we lose to survive. This phenomenon has been referred to as ‘metabolic
adaptation’ many times in the literature and plays a very relevant role in the management of
obesity and human body weight. This review will provide insight into some of the theoretical
models for the etiology of metabolic adaptation as well as a quick look into the physiological and
endocrine mechanisms that underlie it. Nutritional strategies and dietetic tools are thus necessary
to confront these so-called adaptations to weight loss. Among some of these strategies we can
highlight increasing protein needs, opting for high-fiber foods or programming controlled dietrefeeds, and diet-breaks over a large weight loss phase. Outside the nutritional aspects, it might
be wise to increase the physical activity and thus the energy flux of an individual when possible
to maintain diet-induced weight loss in the long-term. This review will examine these protocols
and their viability in the context of adherence and sustainability for the individual towards
successful weight loss.
Keywords: diet-reducing; weight loss; caloric restriction; adaptative thermogenesis; appetite control;
energy balance; energy expenditure; energy intake; metabolic rate; diet refeeds; diet breaks.
1. Introduction
Energy balance could be described as the subtracted difference from the number of calories
consumed by an individual through food intake and the energy expended to maintain his
metabolic and physiological functions and support physical activity and exercise demands (1). If
we conceive the human body as a bioenergetic system, this concept would align with the first law
of thermodynamics, which postures that the total energy of a system is constant, where energy
can be transformed from one form to another, but cannot be created nor destroyed (2). Thus,
modifications over time in energy balance would be the prime determinant of body weight
variation in humans (3). Alongside this concept, successful weight loss in an individual can be
achieved by creating what is known as a caloric deficit or energy deficit, which broadly speaking,
consist in expending more calories or energy than those ingested through food, either by
increasing physical activity or decreasing one’s caloric intake (4). Despite the promotion of
Metabolic adaptation to weight loss
1
different types of diets for weight loss (5,6), the weekly application of the aforementioned
principle (energy deficit) is common amongst all of them and remains the prime determinant
factor for bodyweight reduction (7). Nonetheless, this process is not expected to occur linearly
(8), since it is well documented that macronutrient distribution can affect the magnitude of losses
in the short term (9) and that a series of homeostatic and metabolic adaptations, such as adaptative
thermogenesis(10), changes in mitochondrial efficiency (11) or alterations in the levels of
circulating hormones occur during periods of energy restriction (12). The severity of these
changes will depend on the duration of the dieting period, where longer durations will increase
adaptations; the magnitude of the energy deficit; where higher deficits will promote larger
homeostatic responses; or previous body composition, where lower body fat levels before the
intervention will result in more drastic metabolic adaptations (13,14). It also remains unclearly
answered whether certain nutritional interventions can reduce the severity of the adaptations to
weight loss since the available evidence is reduced, restricted to specific populations (overweight
individuals) and many studies are performed in mice (15,16). Inferring practical applications from
this data may be of relevance for both researchers and practitioners to achieve successful weight
loss in populations who might struggle at manipulating body weight for various reasons (obese
individuals, athletes…).
Aim
It is thus important to understand: (i) the dynamic nature of energy balance, (ii) how these series
of ‘metabolic adaptations’ can affect weight loss and weight regain over time, and (iii) what are
the possible nutritional solutions proposed to mitigate these phenomena. These will be the main
aims of the present review.
2. Evolutionary origins and models to metabolic adaptation
The question still arises as to why our species have been endowed with these modifications to our
physiology during periods of energy restriction. Although the answer is still inconclusive and
mostly dependant on multiple factors, some hypotheses related to our evolutionary past have been
postulated. The ‘Thrifty gene hypothesis’ states that several thousand years back, environmental
pressures and natural selection would favor those who were able to survive long periods of famine
when food was scarce, and thus are the ones who prevailed and conform our genetic heritage, a
heritage that when thrown in our modern ‘obesogenic environment’, lead us to chronic disease
(17). In simple words, ‘Our ancient savior has become our modern issue’. While this theory is an
oversimplification that takes a determinist standpoint and only provides a causal genetic factor
for the development of obesity in our era, it can be used as a conceptual framework to understand
why metabolic adaptation occurs and where it could have come from. Another hypothesis that
aligns with this last one to explain the issue at hand is the existence of a ‘hypothalamic feeding
Metabolic adaptation to weight loss
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center’, more commonly referred as ‘adipostat’, an axis between all of our organs and our central
nervous system that would tightly control food intake in the long term (18,19). This system would
receive afferent signals ranging from hormones (leptin, ghrelin, insulin…) to the gut or adipose
tissue that would help to establish a ‘set-point’ of energy reserves primarily in the form of adipose
tissue and hepatic and muscular glycogen storage thresholds (20,21). This hypothesis has been
generally accepted by the scientific community as a theoretical model to understand the selfregulation of food intake but presents several limitations to explain certain diseases like obesity
(22). The focus of the theoretical models for food intake regulation, however, hasn’t only been
placed on adipose tissue; Millward proposed the existence of a ‘protein-stat’ that would suggest
food intake to be regulated through the needs for maintenance of lean mass (23). Nonetheless, the
evidence for this mechanism is limited. Regarding adaptative thermogenesis (AT), Keys et al.
were the first ones to define this event (24). AT is explained as a spontaneous decrease in energy
expenditure (EE) during weight loss, potentially coming from reductions in the metabolic rate of
some relevant organs (heart, kidneys, brain, liver) and tissues contained within the fat-free mass
(FFM)(25). In one relevant study on this topic (26), it was reported the magnitude of the
adaptation to be around 70-100 kcal/day. Although clinically significant, we must take this data
with caution, since FFM is widely varied in respect to its composition (27), and adjusting for
variables such as the water content of different organs and tissues might affect the previous
calculation. Several methodological limitations arise when accounting for the evaluation of AT
(28). Inter-individual variability was also observed in the Minnesota experiment (26), where
higher baseline EE was associated with higher AT, supporting the notion that the magnitude of
weight loss can be proportional to AT. Nonetheless, the energy expenditure component (which
will be further explained in better detail) where this reduced EE might come from remains unclear
since AT might be coming from the non-resting energy compartment of EE (non-voluntary
reductions in EE through decreases in physical activity), as other models have proposed (29).
Considering this, whether AT is relevant itself or even actually measurable as part of the
metabolic adaptation to weight loss remains disputed (30).
3. Components of energy expenditure
As stated before, a sustained energy deficit over time will lead to weight loss, thus it is important
to precisely describe where total daily energy expenditure (TDEE) of an individual comes from
(31). We can describe at least 2 major components that determine an individual’s TDEE. The first
one, resting energy expenditure (REE), refers to the basal metabolic rate (BMR) and will be the
largest constituent of TDEE in most cases, with an average contribution of 70% to TDEE (32).
This value will depend on many variables such as sex, height, age, physical activity, etc.(33–35)
and although mostly constant through and individual’s lifetime, losses or gains in metabolically
active tissue such as lean body mass (LBM) can contribute to small, though not significant (25),
Metabolic adaptation to weight loss
3
variations in REE (36,37). For research purposes, it should be minded that after approximately
two days of fasting, transient increases in this component (5-10%) can be observed due to an
increase in gluconeogenesis rate (38). The second component is non-resting energy expenditure
(NREE) which is further divided into other 3 minor contributors: exercise activity thermogenesis
(EAT), Non-exercise activity thermogenesis (NEAT), and the thermic effect of food (TEF). The
latter refers to the energy expended during the digestion of food, and its contribution to TDEE is
estimated to be around 10%. However, it should be noted that different macronutrients as well as
other variables (size of meals, processing of foods, duration) contribute separately to this effect,
where bigger meals and higher carbohydrate and protein content can have a larger impact on TEF
(39). This factor might be of consideration when accounting for the TDEE of specific populations,
for instance, high-protein diets for some athletes (40). However, some metabolic chamber studies
in overweight subjects show that even high protein feedings may not pose a significant difference
in TDEE (41), contrary to what could be expected. A commonly held myth regarding TEF is that
a higher frequency of meals will result in increased thermogenesis, but research does not support
this claim (42). EAT would refer to the energy expended during daily, programmed exercise
sessions. This value accounts for little for TDEE (5-10%) and remains unchanged for the most
part unless exercise is ceased or the weight of an individual is reduced significantly (43), thus
needing less energy to support the locomotion required to perform. NEAT is defined as the energy
required to support non-exercise related tasks such as walking and other leisure time activities
(44,45). This component has gathered a lot of attention in recent years, due to its large and variable
contribution to TDEE. NEAT has also been shown to downregulate during periods of energy
restriction (46) and even maintain that state afterward, potentially contributing to weight regain
(47). However, a recent review on the topic (48), aimed to examine the response of NEAT to diet
interventions to promote weight loss, concluding the majority of evidence, despite having relevant
limitations and a high risk of bias, didn’t support a significant reduction in this components. All
TDEE contributors are subjected to some degree of both inter and within-individual variability
(49), where the largest variations in TDEE are dictated by changes in NEAT. If we were to take
NEAT into perspective with the other components, it could represent 15% of TDEE in sedentary
subjects up to 50% in more active individuals (44,50). Figure 1 visually summarizes the different
components of energy expenditure.
Metabolic adaptation to weight loss
4
Components of energy expenditure
REE~5-8%
TEF~20%
EAT~1-4%
NEAT~15-50%
100%
90%
NEAT~15-50%. 15%
80%
EAT~1-4%. 5%
TEF~20%. 10%
70%
%TDEE
60%
50%
40%
30%
REE~5-8%
70%
20%
10%
0%
TDEE
Figure 1. Components of TDEE and their reported coefficients of variation. Note how daily exercise
activity (EAT) is a far-less relevant contributor to TDEE than non-programmed activity (NEAT), despite
the common belief. TEF reports a high variability because it might be dependent on the properties of food
ingested. Adapted from various sources (13,31,49).
4. Physiological responses to weight loss and endocrine modulation of food intake
The energy balance equation remains undisputed for explaining changes in an individual’s body
weight. However, a series of physiological and endocrine alterations occur in response to an
energy deficit that can drive the behavioral response of an individual regarding appetite, satiety,
and food intake, potentially closing the gap between the prescribed energy deficit and the actual
caloric intake. Some of the extreme attempts to reduce weight can be observed in sports where
body weight or aesthetic appearance is relevant for performance outcomes (combat sports,
gymnastics, bodybuilding…). A series of observational and case-report data show many
endocrine and hormonal alterations in athletes who undergo these practices (51–53). These
endocrine profile changes are generally relegated to increases in orexigenic signals and decreases
in anorexigenic pathways to promote food ingestion and restoration of energy homeostasis
(31,54). (Figure 2)
Metabolic adaptation to weight loss
5
Figure 2. A theoretical framework of metabolic adaptation. Note how increases in hunger and slight
reductions in TDEE after long periods of energy restriction exert negative feedback on the initial deficit,
attenuating the degree of weight loss. Adapted from Trexler et al. (13)
It was with the discovery of leptin (55) and its relation with the fat mass that a possible endocrine
role on energy intake was elucidated. We can take leptin, thyroid hormone, insulin, or ghrelin as
examples: Post-prandial leptin levels have been shown to vary over the course of weeks
depending on adipose stores (56). These variations result in increased satiety after a meal
(increased leptin levels/replete adipose stores scenario) or decreased satiety (decreased leptin
levels/depleted adipose stores scenario), potentially regulating subsequential food intake beyond
the conscious control of an individual (57). Leptin has also been shown to modulate hunger by
other means such as inhibiting neuropeptide Y (NPY) and agouti-related protein neurons (AgRP)
or stimulating pro-opiomelanocortin neurons in the hypothalamus (58,59). The thyroid gland
hormones, particularly T3, are also of relevance when accounting for the energy expenditure of
an individual (60). In a cohort of obese children (61), reductions in T3 and T4 levels were
observed after weight losses in the long term, with no variation to TSH. It is important to note
that the levels of these hormones were altered at baseline among some of the subjects included in
the study (two-fold above the standard deviation for their age) and thus it could be debated if
restoration of metabolic homeostasis via reductions in excessive fat-mass was attributable for that
outcome instead of weight loss per-se. In another study of non-overweight subjects (62), it was
reported that those who lost >5% of body weight experimented significant reductions in T3 as
well as in the T3: T4 ratio. Thyroid hormone has also been shown to stimulate brown adipose
tissue (63), which can make small contributions to energy expenditure (64). Insulin is similar to
Metabolic adaptation to weight loss
6
leptin in the sense that both regulate body weight and/or food ingestion via negative feedback
(65) and both have been reported to decrease during periods of energy restriction (66). Insulin
acts in the brain as a potent anorexigenic hormone signaling ‘energy availability’, whereas
peripherally lowers blood glucose levels, driving food intake (67,68). Insulin is also known for
its anti-catabolic properties (69). This is relevant because reductions in FFM have also been
shown to possess a strong orexigenic effect (70) and are now being considered as a potent tonic
appetite signal and a strong driver of food intake after weight loss (71,72). Ghrelin was discovered
in 1999 (73) in the stomach, whose main function is to regulate food intake and serve as an
orexigenic signal. Ghrelin levels have been shown to increase after diet-induced weight loss (74)
as well as upregulate during energy restriction (75). It is thus commonly stated that these transient
orexigenic signals in response to weight loss can drive food consumption and increase appetite
(76). Contrary to leptin, increases in ghrelin production underlie rises in AgRP and NPY
neuropeptides, contributing to its orexigenic effect (77). Regarding ghrelin, this study (78)
reported how the response in circulating levels of ghrelin to meals with different calories wasn´t
equal between obese and lean subjects. Whereas ghrelin levels decreased after high-calorie meals
in the lean group and responsively increased after low-calorie meals (as expected), obese subjects
experimented no significant variation at all (78). This finding highlights how persistent endocrine
alterations (obesity, in this case) can influence the outcomes of studies examining metabolic
adaptation (79). Mechanisms for both leptin and ghrelin resistance in obesity have been reported
elsewhere (80,81). Multiple additional alterations can be observed in the endocrine profile of other
hormones related to appetite and satiety such as gastric-inhibitory polypeptide (GIP) (54) or
amylin (54,82) with weight loss. Peptide YY (PYY) and cholecystokinin (CKK) are
gastrointestinal (GI) peptides that can have an anorexigenic role regarding appetite (83).Their
production is sensitive to size, caloric content, and macronutrient composition of meals (84).
Intervention studies in obese humans report reductions in their respective circulating levels after
a weight loss intervention (85–87), suggesting the notion that these hormones might play a role
in weight regain. Glucagon-like peptide 1 (GLP-1) is secreted in the small intestine in response
to a nutrient load and has direct implications in the regulation of appetite (88). In one study by De
Luis et al. (89) who aimed to examine the effect of weight loss on GLP-1 levels, a positive
relationship between the degree of weight loss and reductions in GLP-1 was observed. In a
different study (90), similar results were observed, where GLP-1 levels decreased after weight
loss compared to baseline. To sum up the information displayed in this section; evidence has been
presented to suggest that reductions in the circulating levels of hormones who might possess an
anorexigenic effect and increments in the ones whose role is mostly orexigenic have been reported
in weight loss intervention trials, both in the short-term and the long-term. This might be reflective
of the body’s attempt to restore energy homeostasis. We must not forget that the sample of the
studies available is not always representative of the general population, let it be the clinically
Metabolic adaptation to weight loss
7
obese or athletes. Thus, effect size and significance cannot be always reliably assessed. The
psychological, behavioral, and environmental aspects regarding weight loss and metabolic
adaptation are out of the scope of this review, however, a proper understanding and management
of these variables is of high relevance (91–93) to achieve successful weight loss. Figure 3 visually
presents an integrative model of the endocrine regulation of appetite and the feedback regulatory
mechanisms that play a role in the dynamic nature of energy balance.
Figure 3. Schematic representation of the endocrine control of energy balance. TDEE: total daily
energy expenditure; EAT: exercise-activity thermogenesis; REE/BMR: Resting energy expenditure/basal
metabolic rate; NEAT: non-exercise activity thermogenesis; TEF: Thermic effect of food; FM: fat mass;
FFM: fat-free mass; CCK: cholecystokinin; PYY; peptide YY; GLP-1: glucagon-like peptide 1. Adapted
from various sources (31,72,94–96).
5. Nutritional strategies to reduce metabolic adaptation to weight loss.
In order to determine the most adequate nutritional interventions to reduce the deleterious effects
of metabolic adaptation to weight loss we must target the main issues responsible for this
phenomenon, which are increased hunger coupled with decreased energy expenditure (13,94,97).
Figure 4 summarizes the ‘energy gap concept’, which explains why hunger and energy
expenditure are the key drivers to design interventions to reduce metabolic adaptation to weight
loss. Higher protein diets, fiber, and intermittent energy restriction protocols (diet refeeds &
breaks) have been proposed as nutritional strategies to have either direct or a non-direct effect on
sustained and successful weight loss. Other factors such as increasing physical activity to maintain
diet-induced weight loss are of utmost importance to reduce our body’s compensatory responses
(98), though this review will focus on the dietetic interventions.
Metabolic adaptation to weight loss
8
Protein
One of the main contributors to the increase in appetite and hunger during energy restriction is
FFM tissue losses, which increases central signaling for food intake (70). Protein is the most
important macronutrient when accounting for the maintenance of FFM and overall health during
lifespan (99,100) and our optimal needs might be increased during periods of dietary restriction
(101,102). To either maintain or increase lean body mass (a component of FFM) the rates of
muscle protein synthesis (MPS) must exceed muscle protein breakdown (MPB) rates (103). A
deeper understanding of protein turnover is out of the scope of this review; the reader is redirected
to other reviews on the topic (104,105). Given the fact that protein might possess a satiating effect
(106,107) and has a higher thermic effect after consumption (108), theory supports increasing
protein intake over usual consumption patterns to mitigate potential increases in hunger and
appetite. In this trial with a randomized parallel design (109) in obese subjects who lost 5-10% of
their total body weight in three months, those who consumed 48g of protein over their usual intake
regained less weight after the follow-up and mainly in the form of FFM. In another study (110),
adding 30g/day of protein to the diet during 7 months resulted in less body weight regained in
overweight subjects. To the author’s criteria, both these studies were well conducted and showed
no important limitations, however, is it important to note the studies were carried out by the same
research group and although the results may be extrapolated with ease, further replication of the
findings is warranted. In the DIOGENES study (111), a randomized controlled trial performed in
Europe with obese and overweight subjects on ad libitum diets, it was reported that after the initial
weight loss, those who consumed a higher amount of protein regained significantly less weight
than those with a lower intake. These results add up to the idea that increased protein might
promote satiety and better weight loss outcomes than a usual intake (112). Several meta-analyses
involving overweight and obese individuals suggest that 1.2–1.5 g/kg is an appropriate daily
protein intake range to maximize fat loss (113–115). It should be reminded that, alongside protein,
exercise plays a relevant role in the maintenance of FFM and the maintenance of energy
expenditure during weight loss. In a randomized controlled trial by Verreijen et al. (116) 100
overweight subjects on hypocaloric conditions underwent either a 10-week program with a high
protein (1,3g/kg) or a low protein diet (0,8g/kg) with or without resistance-type exercise. The
results show how only the group with the combined intervention (high protein & resistance
exercise) preserved a significant amount of FFM. Following this idea, a recent meta-analysis
(117) aimed to determine the effect of different types of exercise on energy expenditure,
concluding that resistance exercise was slightly superior than endurance and aerobic exercise in
increasing energy expenditure. It would also appear that in athletic populations, where the FFM
component is generally larger than that of overweight and sedentary individuals, protein needs
during weight loss might be even higher and of more relevance (118,119) ranging from 1,2g/Kg
Metabolic adaptation to weight loss
9
to 2g/kg of body weight. Mettler et al. (120) found a better retention of lean body mass (skeletal
muscle component of FFM) in individuals who consumed 2,3g of protein/kg/day versus those
who consumed 1g/kg/day during a weight loss protocol. Intakes up to 3,4-4,4g/kg have been
studied before in this population (121–123) with no deleterious health effects and improvements
in body composition reported. However, in the author’s view, such high intakes shouldn’t be
generally recommended since food choices to meet those goals may become unsustainable and
adherence will be compromised. For a more personalized approach, it might be wise to estimate
optimal protein needs based on FFM or lean body mass (124–126) instead of total body weight,
since adipose tissue demands for protein are lower than those of FFM (127). To conclude,
increasing protein intake over usual values might be wise to offset the negatives of dieting over
long periods of time. It is important to understand that recommended dietary allowances (RDA)
establish a minimum, not an optimal intake (128) and thus shouldn`t be taken as a one-size-fitsall recommendation, especially during a caloric deficit. Combining high protein intakes with a
prescribed resistance exercise program appears to be a more interesting intervention to avoid FFM
losses than protein alone (129), and the negative consequences of metabolic adaptation overall.
Fiber
The idea that dietary fiber might help control appetite is still controversial. As a public health
strategy, it is indicated to increase fiber intake (130), since requirements are generally not met.
Evidence from epidemiological studies reports higher fiber intakes to be associated with improved
weight control, higher satiety, and overall lower food intake (131–133). High-fiber foods
generally possess a higher satiety index (134). Possible explanatory mechanisms to this relation
might reside in longer chewing periods to consume high fiber foods as well as its low energy
density (2kcal/g) (135,136). A review with meta-analysis (137) who examined the relation
between acute satiety and consumption of fiber, found no clear relationship between these two
variables in interventional studies. However, there is tremendous variability in the design and
methodology of fiber trials, where different types of fiber may yield different outcomes (138).
High fiber meals can also modulate postprandial concentrations of anorexigenic gastrointestinal
peptides like GLP-1 and PYY (139) thus contributing to increased satiety after a meal. Gastric
emptying rate (GER) is also affected by fiber ingestion as demonstrated by Geliebter et al. (140).
In their study it was reported how oatmeal significantly lowered GER compared to corn flakes
(less fiber than oatmeal) and contributed to greater satiety after the meal. Different and varied
fiber consumption might also contribute to a remodeling of the gut microbiota (141,142) which
present numerous implications in the regulation of food intake and overall health, yet further
investigation is needed about it at the moment. Overall, research on the satiating effects of fiber
has been reported to present numerous methodological limitations and a lack of external validity
(143). Randomized trials with subjects on hypocaloric conditions, with high fiber intakes through
Metabolic adaptation to weight loss
10
a whole-food approach are lacking. Thereby, designing and approach towards increasing fiber in
order to attenuate the effects of metabolic adaptation is complex. Since high-fiber intakes have
been reported to reduce the energy density of the diet (144) as well as allowing for larger volumes
of food without drastically increasing calories (145), fiber could be a useful dietetic tool to attain
an energy deficit.
Diet refeeds and diet breaks
The current US and European (146,147) guidelines recommend continuous energy restriction
(CER) as an effective tool to lose weight. On the other hand, intermittent energy restriction (IER)
includes a series of nutritional protocols that differ from the traditional approach of dieting in a
CER (14), in the sense that they alternate periods of overfeeding with periods of undereating,
which still follow the principles of energy balance (1). The most common IER protocols used are
diet breaks and refeeds. Diet refeeds could be defined as a specific dietetic strategy where calories
and macronutrients are increased at energy maintenance levels or slightly above on specific days
(1-2 days) over the course of a weekly deficit, predominantly achieved by increasing carbohydrate
consumption (13,148). There are several hypotheses to why increasing carbohydrate periodically
could lead to improved weight loss outcomes and better FFM retention; Firstly, since circulating
insulin levels have a role in the maintenance of FFM (69) responses in secretion to acute
carbohydrate refeeds could help reduce muscle protein breakdown (149,150) as well promote a
more pronounced muscle protein synthesis response through the activation of the mTORC1
pathway (151). Secondly, leptin has been demonstrated to be especially responsive to
carbohydrate intake(152). To test if overfeeding alone was solely responsible for the rise in leptin,
this study (153) on lean healthy female subjects, aimed to compare fat versus carbohydrate
refeeds. Plasma leptin levels were elevated after a carbohydrate overfeed but not a fat overfeed,
suggesting carbohydrate to have a major impact on leptin levels. Overweight and obese subjects
may benefit from this strategy since a series of hormonal alterations like leptin resistance have
been reported in this population (154). In this study (155), obese and overweight subjects were
randomly allocated in either an IER restriction group with refeeding every 5 days, a CER group,
or a control group with no advice to restrict calories for 1 year. No significant differences were
observed between the ICR and CER group in regards to weight loss and multiple other
biomarkers, concluding that both protocols were equally effective in weight reduction and disease
prevention(155). In another trial on obese and overweight subjects (156) similar results were
observed, however, reported feelings of hunger were more common among the IER group after 1
year. One key aspect to consider when evaluating different dietary protocols is reported adherence
(157,158). In both studies, the drop-out rate from the participants was reported to be less than
10%, suggesting adherence to IER is similar to CER. Lastly, athletes might benefit more from
intermittent refeeds than overweight subjects as this population has reported favorable results
Metabolic adaptation to weight loss
11
following this protocol (159). This might be due to carbohydrate being pertinent for sports
performance outcomes (160,161). Though not all kinds of sports may require high amounts of
carbohydrate to improve performance (162,163), they are undoubtedly needed for high-intensity
efforts (164,165). In a very recent study by Campbell et al. (166), resistance-trained subjects
followed either a 21% CER or a 26% IER for 7 weeks. Results showed similar reductions in body
weight but higher retention in FFM on the IER group. There are, nonetheless, several
methodological considerations to address when inferring conclusions from the evidence
presented. Adherence was low (27 participants completed the trial from the 58 that were instructed
at baseline), the caloric restriction was different between groups (21% vs 26%) and results were
highly heterogeneous, with subjects losing 3,5Kg of FFM and others gaining 2,5Kg within the
IER group (potentially due to the body assessment methods used). These variables alone might
shift the results of this study towards the null, thus conclusions should be interpreted cautiously.
Diet breaks are similar to refeeds, but differ in the amount of time where energy balance
conditions are met (from 1-2 days up to weeks). Since metabolic adaptations have been shown to
persist even after years after initial weight loss (54), diet breaks are used on the premise that
compensatory responses to weight loss require longer periods in energy balance conditions to
partially or completely return to baseline (167,168). However, evidence for diet breaks is also
mixed: In the MATADOR study (169), 51 obese subjects followed a CER or an IER alternating
weeks of energy balance (14 weeks) with periods of energy restriction (16 weeks) during a total
30 weeks. The results reported greater weight loss among the participants of the IER compared
to the CER group, as other studies have also replicated (170). In contrast, another study (171)
found no difference between diet break protocols over a traditional caloric restriction after 14
weeks. An important consideration to mind about the methodology of the previous study is that
the CER group performed a 2-week break (wasn’t strictly continuous) whereas the IER followed
a 6-week diet break. Since it is not well understood how much time of a break is needed to revert
the compensatory adaptations to weight loss, this factor could have played in favor of the CER
group, thus resembling the outcome. To forge a more solid answer to the question, two recent
meta-analysis (172,173) compared the effects IER to CER regarding weight loss outcomes,
concluding that there was no significant difference between both protocols. It was also reported
how the number of studies included was small and presented huge heterogeneity. Besides, most
of them were at an unclear risk of bias.
Metabolic adaptation to weight loss
12
Figure 4. Visual representation of the energy gap concept. Lowering hunger and increasing energy
expenditure potentially narrows the difference between what’s ingested and what’s expended, thus reducing
the relative magnitude of the energy deficit, ensuring less metabolic adaptation overall while still losing
weight. Taken from Melby et al. (97).
Discussion, practical applications, and concluding remarks.
The postulation of energy balance is a mathematically and scientifically objective concept to
explain changes in human body weight but sometimes incomplete to accurately measure human
energy intake and behavior towards food. Models such as the ‘thrifty gene hypothesis’, the
‘adipostat’ or changes in expenditure compartments during weight loss referred to as ‘adaptative
thermogenesis’ aim to explain those inaccuracies, but all present their respective limitations.
Changes in energy expenditure during weight loss indeed occur but are largely explained by
involuntary changes in the non-exercise activity compartment (NEAT). Alongside changes in
energy expenditure, endocrine and physiological alterations underlying the modulation of appetite
during weight loss comprise reductions in leptin, insulin or FFM, and increases of ghrelin and
gastric orexigenic peptides among many, which represents our organism’s homeostatic drive to
restore balance. Athletes and overweight subjects have shown to respond differently to weight
loss protocols. Where obese subjects might present previous alterations related to energy
homeostasis, leaner athletes usually don’t and thus, slightly different nutritional approaches
should be taken. For example, the higher the previous level of body fat is, the bigger the energy
deficit can be without implying drastic homeostatic adaptations (96), which is the case for obese
subjects. Whereas in lean individuals, faster rates of weight loss are both associated with larger
FFM losses (174) and with an increased risk of fat regain (175,176). Another potential difference
between these two population groups is exercise, since a lack of it, especially resistance-type
exercise, during weight loss results in more pronounced FFM losses (116,177). In regards to
preserving FFM and avoiding negative consequences, high-protein diets ranging from 1,21,5g/Kg in overweight individuals, and up to 2g/kg in leaner ones, have been presented as
effective and secure solutions to aid in the reduction of metabolic adaptation and weight loss.
High fiber foods such as whole grains, fruits, and vegetables are also recommended due to their
ability to generate early satiation and allow for large volumes of food to be consumed while
maintaining an individual on an energy deficit, though more experimental evidence is needed in
Metabolic adaptation to weight loss
13
ad-libitum conditions (143). Concerning diet refeeds and diet breaks, the evidence is mixed and
scarce. However, some positive results for IER have been reported in certain scenarios (166,169)
where both athletes and overweight subjects might benefit from it as a part of a periodized weight
loss program. The disparity of refeeding and diet break protocols used in interventions makes it
harder to establish the superiority of one intervention to the other. However, ensuring proper
adherence, prioritizing carbohydrate over any other macronutrient on refeed days, and
establishing an adequate refeed duration are likely the key factors to consider when implementing
these strategies, yet their direct usefulness as a tool to minimize unwanted compensatory
adaptations to weight loss is still unknown. Non-dietary interventions such as increasing physical
activity energy expenditure and engaging in programmed resistance-training are also advised to
be combined with the aforementioned to further minimize the deleterious effects of metabolic
adaptation to weight loss. As a final remark, the strength and magnitude of the compensatory
responses to dieting appears to be of relevance, at best, in most subjects. Even so and with all the
characterized adaptations that have been described in this review, high individual variability is
observed in studies targeting metabolic adaptation. This might be due to many of the studies on
this topic adopting a biological reductionism perspective. The big picture of metabolic adaptation
engulfs behavioral and psychological aspects related to the subjects many trials fail to properly
address. The accountability of these variables might grant a more solid view of the problem and
therefore its solution. Thus, a proper acknowledgment of the context of the subject, both
overweight and lean, followed by personalized nutritional and exercise advice is the key to
consequently choosing the best possible approach to achieve successful weight loss avoiding the
potential drawbacks associated with it.
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