Is there evidence for a set point that regulates human body weight?

Abstract

There is evidence for the idea that there is biological (active) control of body weight at a given set point. Body weight is the product of genetic effects (DNA), epigenetic effects (heritable traits that do not involve changes in DNA), and the environment. Regulation of body weight is asymmetric, being more effective in response to weight loss than to weight gain. However, regulation may be lost or camouflaged by Western diets, suggesting that the failure of biological control is due mainly to external factors. In this situation, the body's 'set point' (i.e., a constant 'body-inherent' weight regulated by a proportional feedback control system) is replaced by various 'settling points' that are influenced by energy and macronutrient intake in order for the body to achieve a zero energy balance. In a world of abundance, a prudent lifestyle and thus cognitive control are preconditions of effective biological control and a stable body weight. This idea also impacts future genetic research on body weight regulation. Searching for the genetic background of excess weight gain in a world of abundance is misleading since the possible biological control is widely overshadowed by the effect of the environment. In regard to clinical practice, dietary approaches to both weight loss and weight gain have to be reconsidered. In underweight patients (e.g., patients with anorexia nervosa), weight gain is supported by biological mechanisms that may or may not be suppressed by hyperalimentation. To overcome weight loss-induced counter-regulation in the overweight, biological signals have to be taken into account. Computational modeling of weight changes based on metabolic flux and its regulation will provide future strategies for clinical nutrition.

Full text

Is there evidence for a set point that regulates human body weight?
Manfred J Müller
1
*, Anja Bosy-Westphal
1
and Steven B Heymsfield
2
Addresses:
1
Institute of Human Nutrition and Food Science, Christian-Albrechts University, Düsterbrooker Weg 15-17, 24221 Kiel, Germany;
2
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
* Corresponding author: Manfred J Müller (mmueller@nutrfoodsc.uni-kiel.de)
F1000 Medicine Reports 2010, 2:59 (doi:10.3410/M2-59)
The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/medicine/content/2/59
Abstract
There is evidence for the idea that there is biological (active) control of body weight at a given set
point. Body weight is the product of genetic effects (DNA), epigenetic effects (heritable traits that do
not involve changes in DNA), and the environment. Regulation of body weight is asymmetric, being
more effective in response to weight loss than to weight gain. However, regulation may be lost or
camouflaged by Western diets, suggesting that the failure of biological control is due mainly to
external factors. In this situation, the body’s‘set point’(i.e., a constant ‘body-inherent’weight
regulated by a proportional feedback control system) is replaced by various ‘settling points’that are
influenced by energy and macronutrient intake in order for the body to achieve a zero energy
balance. In a world of abundance, a prudent lifestyle and thus cognitive control are preconditions of
effective biological control and a stable body weight. This idea also impacts future genetic research on
body weight regulation. Searching for the genetic background of excess weight gain in a world of
abundance is misleading since the possible biological control is widely overshadowed by the effect of
the environment. In regard to clinical practice, dietary approaches to both weight loss and weight gain
have to be reconsidered. In underweight patients (e.g., patients with anorexia nervosa), weight gain is
supported by biological mechanisms that may or may not be suppressed by hyperalimentation. To
overcome weight loss-induced counter-regulation in the overweight, biological signals have to be
taken into account. Computational modeling of weight changes based on metabolic flux and its
regulation will provide future strategies for clinical nutrition.
Introduction and context
Since body weight is a major determinant of health, the
regulation and preservation of body composition are
life-saving issues. The central nervous system and
peripheral systems regulate energy and nutrient balance
by biological and behavioral mechanisms. Short-term
controls include the initiation and termination of
feeding (e.g., brought about by gastrointestinal signals),
whereas long-term control of body weight is related to
changes in energy balance and energy stores. Efficiency
of body weight regulation is dominated by both sides of
the energy balance (both energy intake and energy
expenditure), which are functionally interconnected.
Thus, increases in either food intake or energy expendi-
ture are associated with corresponding changes in
metabolism and behavior. Overeating is followed by
increases in thermogenesis, whereas increases in energy
expenditure (e.g., due to strenuous exercise) affect food
intake. The general idea is that human body weight is
under sufficiently strong genetic and humoral control, a
view inspired by the theory of the so-called ‘set point’.
This theory proposes a proportional feedback control
system designed to regulate body weight to a constant
‘body-inherent’weight, namely the set point weight [1].
The system, according to this theory, adjusts food intake
or energy expenditure (or both) in proportion to the
difference between the current body weight and the
set point weight. The set point theory originated from
animal studies [2] and ever since has been questioned in
humans.
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Many people appear to have a constant body weight
throughout adult life. However, intervention studies
suggest that a set point in humans is ‘loose’(e.g., involving
upper and lower limits) rather than tightly controlled [3].
In the classical Minnesota starvation study [4], the subjects
lost 66% of their initial fat mass in response to 24 weeks
of semi-starvation (i.e., at 50% reduced energy intake), but
ad libitum re-feeding resulted in a regain of fat mass
reaching 145% of the pre-starvation values (i.e., there was
an overshooting of fat mass, known as the catch-up fat
phenomenon) [5]. Thus, the fluctuation in body weight
that results from under- and overfeeding requires a
considerable change in the hypothetical set point, at
least after starvation, re-feeding, and overeating. Alter-
native models of body weight regulation therefore (a)
involve multiple body weight steady states, so-called
‘settling points’, without a feedback control of energy
intake [1] or (b) propagate an asymmetric or threshold
control system that responds to negative energy balance
only [2].
Further simulation of the Minnesota starvation experi-
mental data suggested that after re-feeding, it may take
more than a year for the fat mass to decrease to within
5% of the initial value [6,7]. These data point to a
transient loss in appetite control (and thus body weight
regulation) during the first months of re- and over-
feeding. Returning to a pre-starvation (and presumably
healthy) lifestyle may take longer time periods as the
body reconstitutes or resets its body weight regulatory
system. This finding may lead to the more general
hypothesis that the biology of body weight regulation is
camouflaged by hyperphagia (and presumably a Western
lifestyle).
Control of energy intake is a complex topic and this
control is something that many overweight people lose in
the long term. This is reflected by nearly all of the weight
loss experiences of obese patients who typically lose their
diet adherence with time [8]. Obviously, at reduced body
weight, a new set or settling point is hard to establish
(or hard to defend). It has been calculated that in weight-
reduced obese patients, maintenance of lost body weight
would have been achieved if energy intake over the course
of 2 years had been 170 kcal/day (0.7 MJ/day) lower than
before dieting [7]. The failure of keeping these small
changes in diet, and thus of maintaining a reduced weight,
may be taken as evidence for the inaccuracy or even
inefficiency of our weight control system to defend the
‘new’settling point. Alternatively, the programmed
regaining of body weight may also be taken as evidence
for a high set point, which seems to be well defended in
most obese patients.
The data from randomized controlled pharmacological
weight loss trials question the existence of a body weight
control system. When compared with dietary restriction
alone, a cannaboid-1 receptor blocker caused significant
weight loss over the course of 2 years (−6.3 kg versus
−1.6 kg compared with pre-study weights) [9]. However,
patients who were switched from the drug to the diet
group in the second year of the protocol regained weight
and reached nearly identical weight losses after the second
year (−2.7 kg versus −2.9 kg by diet alone compared with
pre-study weights) [9]. These data may be taken as
evidence for different settling points. Alternatively, weight
changes simply followed energy intakes (which were lower
during drug treatment than during diet alone) and the
final body weights then reflected a new and zero energy
balance.
There are some lines of evidence suggesting that the
traditional set point theory seems to be overly simplistic.
The present article sets out to address the following
questions:
1. Is there evidence for a set point in body components
(rather than in body weight)?
2. Is there a ‘set’in energy balance and macronutrient
metabolism?
3. Is leptin a body weight regulatory signal, and what is
the evidence for asymmetric control of body weight?
4. Does a Western lifestyle camouflage biological
regulation of body weight?
Recent advances
Recent advances arose from the area of detailed body
composition research and from recent findings on the
genetic, epigenetic, and endocrine control of body
weight (i.e., leptin as part of the body weight regulatory
system). To put these data into perspective, the new
results have to be discussed within the context of some
older results from integrative physiology which have
frequently been neglected in modern research on genetic
control of body weight.
The contribution of gene variants to body weight
regulation is currently estimated to be small, and most
genome-wide association results are for markers that
are not in known genes [10]. In addition, metabolic
programming and epigenetic influences add to body
weight regulation. The developmental origins of the
health and disease hypothesis (i.e., the fetal programming
hypothesis) speculate that maternal over- and under-
nutrition affect the in utero environment thereby inducing
fetal adaptive responses favoring long-term and
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permanent changes in hypothalamic circuits of appetite
regulatory centers, post-natal overnutrition, and excess
weight gain in the offspring [10]. Genomic imprinting
(including DNA methylation and histone modification)
results in later discordance between metabolic responses
anticipated by the program and the environment. This
idea is supported by a recent study that found that, when
comparing the offspring of obese mothers with those of
obese mothers who had lost weight following biliopan-
creatic bypass surgery, the prevalence of offspring who
were overweight was reduced by 52% after maternal
biliopancreatic bypass surgery [11]. These data point to the
role of epigenetic factors in the regulation of body weight.
A major recent advance is computational modeling of
weight changes based on metabolic fluxes and their
biological control. This will add to future strategies of
pharmacological and non-pharmacological treatment of
clinical problems of being over- or underweight. Today,
it seems likely that the phenotype (i.e., an obese body
mass index [>30]), influenced by set or settling points, is
the product of genetic effects (DNA), epigenetic effects
(heritable traits that do not involve changes in DNA),
and the environment.
Is there evidence for a set point in body components
rather than for body weight?
Body weight is heterogeneous in that it comprises many
different organs and tissues. In a two-compartment model,
body weight is the sum of body fat mass and lean or fat-
free mass. Lean mass consists of bone, extracellular water,
and body cell mass; body cell mass includes intracellular
water, glycogen, and protein. Anatomically, lean tissue
comprises a number of individual organs or components
such as skeletal muscle, liver, brain, heart, and kidneys. In
a 70-kg male, these components make up 40%, 2.6%,
2.0%, 0.5%, and 0.4% of body weight, respectively [12].
Some component weights are interrelated (e.g., there is
a positive correlation between muscle mass and bone
mass), but for other components (including bone and
brain), their weights are not associated with each other
[13]. This lack of association argues against a common
regulation of the mass of individual organs and tissues and
therefore overall body weight. Instead, it appears more
likely that individual organ and tissue mass are differently
regulated.
Body weight regulatory feedback may originate from fat
mass [2,5]. Both surgical lipectomy and transplantation
of white adipose tissue in animals result in compensatory
changes to defend total body fat [14]. In the Minnesota
study, post-starvation hyperphagia was related to the
extent to which body fat was depleted [4,5], suggesting
that the drive to overeat is part of a regulatory system that
operates to restore fat mass. In addition, there is sufficient
evidence for humoral feedback signals that influence
body fat mass, and studies of extreme human obesity
phenotypes (i.e., children who are obese from a very early
age) suggest that the efficiency or inefficiency with which
these processes operate may be heritable [15]. However,
adipose tissue is heterogeneous with respect to location,
amount present, metabolic functions, and response
to weight changes [16,17]. This concept implies that a
search for regulation of individual adipose tissue depots
rather than of total body adipose tissue is necessary.
There is some recent evidence suggesting that adipose
tissue distribution is genetically (or epigenetically)
programmed [18]. Diet-induced weight loss in over-
weight subjects does not affect adipose tissue distribu-
tion, implying that the different depots (e.g., visceral and
subcutaneous) are reduced with weight loss [16,17,19].
However, there are preferential losses of visceral adipose
tissue [20] and ectopic fat in the liver and these are
disproportionately depleted with weight loss [17].
Is there a ‘set’in energy balance and macronutrient
metabolism?
Increasing energy expenditure can increase energy intake,
whereas increasing energy intake does not intrinsically
increase activity and energy expenditure [21]. However,
with strenuous exercise and very high energy expenditure,
energy intake cannot be adjusted adequately and the
energy balance becomes negative [22]. Metabolic com-
pensation is obvious during controlled under- and
overfeeding (i.e., during rapid changes from energy
equilibrium to a negative or positive imbalance)
[23-25]. With underfeeding and weight loss, total (i.e.,
24-hour) energy expenditure (TEE), resting energy
expenditure (REE), the thermic effect of meals, and
physical activity (PA) decrease [4,6,24-26], whereas
increases in TEE and REE (but not PA) are observed in
response to overfeeding and weight gain [6,23,25,27].
Metabolic changes exceed changes in metabolically active
tissue mass (i.e., they were not explained by changes in
body mass) and thus are partly due to decreasing or
increasing the rate of cellular respiration. The whole-
body metabolic response to under- and overfeeding is
brought about by an interplay of metabolic rates in
individual organs (e.g., heart, liver, kidneys, skeletal
muscle, and brain), and this again is explained by
changes in sympathetic nervous system activity, in
plasma concentrations of thyroid hormones and leptin,
and in insulin sensitivity [7,28]. These metabolic
adaptations aim at diminishing the energy imbalance
(to finally reach a new equilibrium between energy
intake and energy expenditure) and thus add to long-
term weight stability [29]. This idea argues in favor of a
‘set’to reach zero energy balance at a given body weight,
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which results in various settling points rather than a set
point.
In regard to the comparison of different energy stores, fat,
protein, and carbohydrate stores differ with respect to
both (a) magnitude (i.e., in a 70-kg male, about 140,000
kcal [or 586 MJ] as fat, 24,000 kcal [100 MJ] as protein,
600 kcal [2.5 MJ] as carbohydrate) and (b) regulation
[29]. In the long term, carbohydrate balance is tightly
regulated and a glycogen feedback signal acts to correct
glucose oxidation and thus carbohydrate imbalances
[23,30]. Thus, a minor decrease in liver glycogen (e.g.,
brought about by a low-carbohydrate, high-fat diet)
increases the eating drive in order to replenish glycogen
stores (which will also take a large amount of fat and thus
increase fat mass in the case of a low-carbohydrate, high-
fat diet) [31]. By contrast, protein and fat imbalances are
not tightly counter-regulated, leading to greater losses or
gains in these individual components in response to
nutrient intake. Whole body and cellular uptake of dietary
carbohydrates, fat, and protein is matched by their rates
of use. There is a hierarchy of post-prandial substrate
oxidation, and fat intake did not stimulate fat oxidation
[32,33], and this explains large fluctuations in fat mass in
response to varying fat intakes [33]. Taken together, these
data suggest that carbohydrate balance, rather than
protein and fat balance, is regulated as part of a putative
body weight regulatory system. If glycogen stores serve as
a‘set’for body weight, then variation in body weight is a
reflection of the fat content of the diet rather than of an
active regulation.
Is leptin a feedback signal of body weight regulation?
What is the evidence for asymmetric control?
During the last 15-20 years, the progress in our under-
standing of the neurobiology of appetite and satiety
has led to the characterization of fascinating networks
of hormones, peptides, and monoamines as part of the
appetite control system. However, endogenous control of
energy intake is still not completely characterized and
external factors (i.e., the obesity-promoting environment)
may override endogenous controls. It is unknown at
present how biological factors (e.g., hormones) combine
with external factors (e.g., food supply) to control food
intake. In addition, the impact of metabolic adaptation
on energy and macronutrient intake remains to be
characterized.
Most of the recent research on body weight regulation is
based on the idea that brain centers, including those
located in the hypothalamus, receive peripheral signals
reflecting energy and fat stores. Early parabiosis studies
gave the first strong evidence that genetically obese
mice lacked a secretory signal from adipose tissue which
represses food intake [34]. One relevant homeostatic
signal in body weight (or fat mass) regulation is the
prototype adipokine leptin [35,36]. Leptin is derived
from fat cells in proportion to fat mass, and one of
leptin’s tasks is to send signals regarding levels of fat
mass (or changes in fat mass) to the hypothalamus,
which in turn regulates both a decrease in energy intake
and an increase in energy expenditure. This is an example
of proportional feedback control, as food intake and
energy expenditure are adjusted in proportion to the
difference between plasma leptin concentration and its
set point value [1]. However, present evidence suggests
that leptin does not primarily protect the body against
an increase in fat mass but instead defends the body
against fat loss, thus operating in cases of negative energy
balance only (i.e., there is an asymmetric or threshold
response to leptin at low concentrations only) [2,37,38].
Low levels of leptin, indicating food deprivation and
depleted fat stores, are a signal to induce adaptive
biological actions leading to an increase in energy intake
(which cannot or does not happen in the case of food
shortage or eating disorders) and to reduce energy
expenditure [39,40]. For example, the correlation line
demonstrating the relationship between leptin and REE,
adjusted for fat-free mass, is steep at low leptin levels and
flat at normal leptin levels, suggesting that the effect of
leptin on REE differs at different leptin concentrations
with a thermic effect at low concentrations only [40].
This example highlights that the control of individual
body component mass (e.g., fat) depends on energy
balance and may be efficient in response to negative
energy balance and fasting only. An asymmetric control
system is in line with the experience that it is easier to
gain weight than to lose weight. While the latter is tightly
controlled, the former seems to be not fully compen-
sated. This idea also questions the hypothesis that leptin
resistance, as suggested by high-plasma leptin levels,
causes obesity.
Does a Western lifestyle camouflage biological regulation
of body weight?
Observational and experimental human data give some
evidence for biological control of body weight. However,
given the present obesity epidemic, this may reflect a
collective overwhelming of the biological body weight
control systems. In fact, biological ‘brakes’are considered
to be weak and do not really operate within an obesity-
promoting environment. This failure is part of the so-
called ‘runaway weight gain train’model that has been
proposed to perpetuate obesity and to further accelerate
the obesity epidemic [41]. However, on a daily balance,
excess weight gain is a failure in the fine tuning of energy
balance, and obesity results from a chronic (but small)
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positive energy balance. The so-called energy gap (i.e.,
the daily imbalance between energy intake and energy
expenditure, resulting in excess weight gain) is about
50-150 kcal/day (0.2 to 0.6 MJ/day) only (corresponding
to 5% of daily energy intake) [42,43]. This is in line with
longitudinal data showing that a difference in energy
expenditure of about 70 kcal/day was associated with
differences in weight gain [44]. All of these data point to
the need of precise matching between energy intake and
energy expenditure. Thus, a mismatch between the two
suggests that regulation is not precise. Some of the
metabolic changes observed in overweight subjects
(e.g., increases in energy expenditure and fat oxidation)
contribute to limiting further weight gain in response
to chronic overeating and aim to reach a new steady state
(i.e., at a settling point) rather than to re-establish initial
body weight [29]. It is obvious that under Western
lifestyle conditions, compensatory responses are passive
rather than active and thus have a limited impact on
body weight regulation.
It is tempting to speculate that imperfect body weight
control is due to our present lifestyle habits, which offset
biological control. This idea is in line with animal studies
in which so-called cafeteria (or Western) diets resulted
in hyperphagia (i.e., the animals lost intake control),
progressive weight gain, and obesity when compared
with a normal chow diet [45]. Switching back again to a
chow diet, the rats normalized their body weights (i.e.,
the animals readjusted their weights to previous levels),
and in the long term, this resulted in a normal weight
trajectory [45]. This is in line with human data showing
that energy-dense foods, which are rich in fat and sugar,
cause ‘passive’overeating and thus weight gain [46]. By
contrast, an ad libitum, low-fat, high-carbohydrate,
traditional diet led to a spontaneous return to habitual
energy intake (within 3 months) and a recovery of initial
body weight (within 2.5 years) after massive overfeeding,
with 19 ± 3.2 kg weight gain in lean young Cameroonian
men [47]. A set point regulation was also evident under a
traditional low-fat diet and seasonal fluctuations (caused
by an annual food shortage) in the body weight of rural
Gambian women [48]. Despite repeated weight cycling
over a period of 10 years, minimal body weight
remained fairly stable (within ± 1.5 kg).
Implications for clinical practice
In regard to clinical practice, dietary approaches to both
weight loss and weight gain have to be reconsidered. In
the underweight patient, weight gain is supported by bio-
logical mechanisms that might be suppressed in part by
aggressive hyperalimentation. By contrast, to overcome
weight loss-induced counter-regulation in the overweight,
biological signals (i.e., the weight loss-associated decrease
in plasma leptin and T3 [triiodothyronine] levels) have to
be taken into account. Evidence suggests that leptin
replacement may help to reconstitute biological control.
In addition, modeling of weight changes (e.g., in patients
with cachectic cancer) [49] based on biological control of
body weight provides new concepts in pharmacological
and non-pharmacological treatment of the underweight.
‘Set point and settling points’instead of ‘set point
versus settling point’
Taken collectively, these data provide evidence for the
idea that there is biological (active) control of body
weight and also weight stability (and thus a set point at a
healthy steady state) in response to eating healthy chow
diets. By contrast, this regulation is lost or camouflaged
by Western diets, suggesting that the failure of biological
control is due mainly to external factors. In this situation,
the set point is replaced by various settling points that
are influenced by energy and macronutrient intake in
order for the body to reach a zero balance of energy and
macronutrients and thus a new and possibly unhealthy
steady state. Western diets may have a higher risk in
subjects who are efficient in the intake or metabolism of
food energy, the so-called thrifty genotypes, who have
been proposed to have a genetic predisposition or a high
set point. However, the present evidence from integrative
physiology leads to simple rather than to sophisticated
answers. In a world of abundance, a prudent lifestyle and
thus cognitive control (i.e., ‘from instinct to intellect’)
[50] are preconditions of efficient biological control, a
stable body weight, and thus maintenance of a set point.
This idea is true even in those people who may have an
efficient intake or metabolism of food energy (i.e., the
thrifty genotype) [10] since the putative mutation is
effective at high energy and fat intake only. In this sense,
losing one’s set point (or ending up in various settling
points) of body weight may serve as another example of
the ‘mind-body paradigm’(e.g., in the obese, there is a
‘mind-body gap’and thus a loss of biological control).
This idea also impacts future research on body weight
regulation. Searching for the genetic background of
excess weight gain in a world of abundance is misleading
since the possible biological control is widely over-
shadowed by the effect of the environment. As a
consequence, environmental factors rather than the
physiology (including the genetic background) have to
be addressed to tackle population-wide, non-syndromic
human obesity. It is interesting to note that the
fundamental components of energy balance, including
the effect of the environment, are well preserved across
species. For example, canine obesity is closely associated
with snack eating and low socioeconomic state, suggest-
ing that the overweight issue is not a uniquely human
problem [51].
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Abbreviations
PA, physical activity; REE, resting energy expenditure;
TEE, total energy expenditure.
Competing interests
The authors declare that they have no competing
interests.
Acknowledgments
Our own data were supported by ‘Competence Network
on Obesity’, funded by the Federal Ministry of Education
and Research (FKZ: 01GI0821) and the Deutsche
Forschungsgemeinschaft (German Research Founda-
tion) (DFG Mü 714/8-3 and DFG Bo3296/1-1).
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