WALTHAM International Science Symposium:

Nature, Nurture, and the Case for Nutrition

Obesity: The Integrated Roles of Environment and Genetics1,2

John R. Speakman3
Aberdeen Centre for Energy Regulation and Obesity, Division of Energy Balance and Obesity, Rowett
Research Institute, Aberdeen AB21 9SB, Scotland and School of Biological Sciences, University of
Aberdeen, Aberdeen AB24 2TZ, Scotland

ABSTRACT Obesity represents one of the most serious global health issues with ;310 million people presently
affected. It develops because of a mismatch between energy intake and expenditure that results from behavior
(feeding behavior and time spent active) and physiology (resting metabolism and expenditure when active). Both of
these traits are affected by environmental and genetic factors. The dramatic increase in the numbers of obese people
in Western societies reflects mostly changing environmental factors and is linked to reduced activity and perhaps
also increased food intake. However, in all societies and subpopulations, there are both obese and nonobese
subjects. These differences are primarily a consequence of genetic factors as is revealed by the high heritability for

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body mass index. Most researchers agree that energy balance and, hence, body weight are regulated phenomena.
There is some disagreement about exactly how this regulation occurs. However, a common model is the ‘‘lipostatic’’
regulation system, whereby our energy stores generate signals that are compared with targets encoded in the brain,
and differences between these drive our food intake levels, activity patterns, and resting and active metabolisms.
Considerable advances were made in the last decade in understanding the molecular basis of this lipostatic system.
Some obese people have high body weight because they have broken lipostats, but these are a rare minority. This
suggests that for the majority of obese people, the lipostat is set at an inappropriately high level. When combined with
exposure to an environment where there is ready availability of food at low energy costs to obtain it, obesity develops.
The evolutionary background to how such a system might have evolved involves the evolution of social behavior, the
harnessing of fire, and the development of weapons that effectively freed humans from the risks of predation. The
lipostatic model not only explains why some people become obese whereas others do not, but also allows us to
understand why energy-controlled diets do not work. Drug-based solutions to the obesity problem that work with the
lipostat, rather than against it, are presently under development and will probably be in regular use within 5–10 y.
However, several lines of evidence including genetic mapping studies of quantitative trait loci associated with obesity
suggest that our present understanding of the regulatory system is still rudimentary. In particular, we know nothing
about how the target body weight in the brain is encoded. As our understanding in this field advances, new drug
targets are likely to emerge and allow us to treat this crippling disorder. J. Nutr. 134: 2090S–2105S, 2004.

KEY WORDS:  obesity  genetics  environment  review

Background
It is an ironic and rather sad fact that the two major
nutritional problems that presently face the world are that
1
Presented as part of the WALTHAM International Science Symposium:
Nature, Nurture, and the Case for Nutrition held in Bangkok, Thailand, October
28–31, 2003. This symposium and the publication of the symposium proceedings
were sponsored by the WALTHAM Centre for Pet Nutrition, a division of Mars, Inc.
Symposium proceedings were published as a supplement to The Journal of
Nutrition. Guest editors for this supplement were D’Ann Finley, James G. Morris,
and Quinton R. Rogers, University of California, Davis.
2
My work on obesity has been generously supported by the Scottish
Executive, the Biotechnology and Biological Sciences Research Council of the
UK (Grant 1/S12830), and the Wellcome Trust. I am grateful to the organizers of
the 2003 WALTHAM International Symposium for the invitation to present this work
as a plenary address.
3
To whom correspondence should be addressed. E-mail: j.speakman@rri.
sari.ac.uk.
;600 million people face severe energy deficits and starvation
while at the same time, ;310 million people face a problem of
chronic energy surplus and obesity (1). In some cases, these
problems exist alongside one another (2), but obesity is
predominantly a problem of Westernized societies. In the last
few years it has become an increasing problem throughout most
of the world (e.g., 3–6). By 2000 the obesity problem had
already grown to such an extent that the World Health
Organization declared it was the greatest health threat facing
the West (7). Obese people carry around excessive amounts of
body fat, which in the absence of more direct measures, is
generally estimated by combining measures of height and
weight. The most common method of combining these
measures is to divide body weight in kilograms (W) by the
height in meters (h) multiplied by itself (i.e., W/h2). This is

0022-3166/04 $8.00 Ó 2004 American Society for Nutritional Sciences.

2090S
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
called the body mass index (BMI)4. On the BMI scale, people
with an index .25 but ,30 are said to be overweight, and
people with an index .30 are defined as obese. Although these
definitions have been adopted by the WHO, there are several
well-recognized problems with this index. In particular, it does
not reflect body fatness changes very well when a person is also
changing his or her height over time. Consequently, BMI
cannot be used to reliably gauge the body fatness of children. In
addition, bodybuilders and some athletes, who have developed
large amounts of muscle tissue, may also be misclassified as
obese. Generally, however, in most adults, BMI correlates
reasonably closely to body fatness (which is measured by more
sophisticated scanning and imaging devices), particularly if
combined with measures such as the waist circumference (8).
Despite its limitations, the preferred use of BMI is justified
on historical grounds. During the 1930s, U.S. life insurance
companies analyzed the factors that influence the probability
that someone would redeem a life insurance policy (which
generally meant a person had died). Based on redemptions of
;5,000,000 policies issued in the 1930s, the factor the
companies decided was the most effective predictor of mortality
was BMI. In fact, the life insurance companies discovered that
mortality was lowest for individuals with BMIs between 20 and
25. Above this range, mortality increased, and it increased
dramatically when BMI was .30. Conversely, mortality also
increased when BMI fell to ,20. This pattern of increase at
high and low BMIs is at least partly influenced by the
heterogeneous nature of the population involved, which
included both smokers and nonsmokers (9). Smokers domi-
nated the low-BMI classes throughout the 1940s–1960s, before
the health effects of smoking were widely acknowledged. When
only nonsmokers were examined, the dramatic rise in mortality
at low BMI was much reduced although not entirely removed.
The normal BMI range for minimal mortality in nonsmokers is
presently suggested to be from 18.5 to 24.9 (7).
Effects of obesity on mortality
Among both smokers and nonsmokers, mortality increases
as BMI increases .25. This is because there is a direct link
between body fatness and susceptibility to many degenerative
diseases (6,10). The most important of these is type 2 diabetes.
The risk of developing type 2 diabetes for someone with a BMI
of 35 compared to someone with a BMI of 22 is 40–90-fold and
appears to be greater in obese females than males (11).
Diabetes increases the risk of circulatory disorders and
cardiovascular disease and is the most common cause of
blindness in people aged ,60 y. Increased body fatness is also
an independent risk factor for hypertension and cardiovascular
disease. Some cancers (particularly breast cancer) are increased
in relation to body fatness, although whether this is a problem
of impaired early detection using existing techniques in the
obese patient is not clear. Obesity is also a risk factor for several
respiratory disorders including sleep apnea (12). The obese
patient is more likely to be depressed and taking antidepressant
medications, more likely to suffer joint problems, and also more
likely to suffer from skin disorders.
4
Abbreviations used: AgRP, Agouti-related protein; a-MSH, a-melanocyte–
stimulating hormone; ARC, arcuate nucleus; BMI, body mass index; BMR, basal
metabolic rate; CART, cocaine and amphetamine–related transcript; db/db, mutant
mouse lacking functional leptin receptors; fa/fa, mutant rat lacking functional leptin
receptors; GABA, g-amino butyric acid; MC1-R, MC3-R, and MC4-R, melano-
cortin-1, -3, and -4 receptors; NPY, neuropeptide Y; ob/ob, mutant mouse lacking
ability to produce leptin; POMC, pro-opiomelanocortin; PVN, paraventricular
nucleus; PYY3-36, peptide YY3-36; QTL, quantitative trait loci; RMR, resting
metabolic rate; TNF-a, tumor necrosis factor-a; tub/tub, fat mutant mouse.
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Because of the medical complications associated with
obesity, there is a statistically significant increased risk of
mortality once BMI increases .25. Because the original data
were derived for mostly white persons living in the U.S., there
has been recent discussion over the relevance of this cut-off
point for different ethnic groups (13). In particular, in Asians
and Chinese, mortality has already started to increase at a BMI
of 23–24. If a person has a BMI .30, then on average, his or her
expected life span is reduced by 9 y compared to someone with
a BMI of 20–22 (14). There are ;30,000 premature deaths in
the UK annually that can be attributed to obesity (14). For
comparison, this is about the same number of individuals who
die of lung cancer (;33,000 annually). Throughout Europe,
the deaths attributable to obesity exceed 300,000 annually,
which is ;1 in every 13 recorded deaths (15).
The health consequences of obesity combined with the fact
that large numbers of people are afflicted by it has significant
economic consequences. In the UK, these costs were quantified
in 2000 by the National Audit Office (13) to be ;£500 million
annually in direct health care costs and a further £2 billion
annually in wider costs to the economy. In the U.S., the total
economic costs of obesity in 1997–1998 were estimated at
;$92.6 to 99.2 billion annually when normalized to 2002
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dollars (16–18). Similar data are available for most Western
societies that indicate the present costs of obesity generally run
at ;5–8% of heath-care spending (18–22).
The effects of obesity on health outcome appear to be
reversible if the person in question loses weight. This is
important, because it is not entirely clear yet what the
mechanisms are by which obesity predisposes someone to
a particular disease. Based on the correlative evidence alone,
obesity might be linked to elevated disease risks by a genetic
pleiotropy; that is, a genetic problem leads a person not only to
develop obesity, but the same problem, in association with
a Western lifestyle, independently elevates the disease risk. If
this were true, simply reducing the level of body fatness would
not remove the underlying cause of the elevated disease risk.
However, several recent studies consistently show im-
provements in associated health outcomes for people who were
obese but have sustained weight loss for protracted periods.
Consequently, it is obesity itself and not a shared underlying
genetic lesion that causes elevated disease risk.
The exact mechanisms by which obesity leads to the
development of disease is an area of intense study. This is
because it is not obesity itself but rather the health
consequences that are the issue. If the nature of the causal
link between obesity and health problems could be elucidated,
then developing therapies that break that link might be
a feasible solution to the problem. This is obviously attractive,
because it would mean people could continue to pursue
a Western lifestyle while avoiding the negative consequences.
There are two basic alternatives that have been proposed to
link obesity with diabetes. The first suggests that because
obese people have much higher circulating levels of free fatty
acids, in muscles, these might compete with circulating
glucose. This leads to persistently elevated circulating glucose
levels, elevated insulin secretion, and ultimately, insulin
resistance. The alternative suggestion is that some products
secreted by fat tissue actively interact with insulin to generate
insulin resistance or promote insulin sensitivity. Some
important secretions from adipose tissue in this respect are
TNF-a (23,24), adiponectin (25,26), and resistin (26,27).
Blocking the signals that link obesity to diabetes may be an
effective therapy for obesity-mediated diabetes, but this
approach is only likely to address one disease consequence at
a time. Hence, a much more useful approach is to actually try
2092S SUPPLEMENT
to eliminate all the disease consequences at once by treating
obesity itself.
Energy balance and obesity
Obesity is a problem of imbalance between energy intake
and expenditure. Total energy demands can be partitioned into
several different compartments. The requirement to sustain
general cellular processes is known as the basal metabolic rate
(BMR). BMR is measured under strict conditions whereby the
subject is completely inactive, is not digesting food, and is at
a thermoneutral temperature. If we sit quietly, we burn more
energy than BMR, and this is generally called the resting
metabolic rate (RMR). After food ingestion, our metabolic rate
rises further; when we start to move around, it increases even
more and is termed active energy expenditure. To balance our
total energy expenditure, we eat food. In the short term,
expenditure and intake do not match closely, because we feed
in discreet bouts, whereas expenditure is a continuous process.
Because of the laws of thermodynamics, which state that energy
can neither be created nor destroyed, the imbalance between
intake and expenditure requires that we also have the capacity
to temporarily store energy. Generally, the equation is food
energy intake 5 energy expenditure 1 energy storage. We store
energy as fat, because it is much denser than carbohydrate and
also does not require large amounts of water for storage. Given
the energy-balance equation, it is clear that obesity results from
either food intake being too high, expenditure being too low
(through low RMR and/or activity expenditures), or a combi-
nation of both.
The obesity phenomenon is usefully considered as having
two different facets. The first is the temporal trend in the
prevalence of overweight and obese people over time,
particularly over the last 25 y. Most people alive today (in
2004) were also alive in 1980. Consequently, the expansion of
the prevalence of obesity between 1980 and 2004 must reflect
changes that have occurred in our behavior (activity and food
intake) that are dependent on the changing environment
rather than the effects of population genetics. The second facet
is the differential susceptibility of individuals to the problem.
Whatever environment or time period we choose, we find a mix
of obese and lean people. These differences may reside in the
microstructure of the environment experienced by each
individual or may depend on genetic differences. An important
point to recognize is that genetics and environmental factors
exert their effects on energy balance and obesity via effects on
our behavior and physiology (Fig. 1). There is no direct link
between our genes and our body weight or fatness. This is
frequently misunderstood as is evidenced by discussions about
whether obesity is caused by our genes or our behavior (e.g.,
28). As Figure 1 makes clear, these are not alternative causal
agents. Behavior and genes are different levels of the same
causal framework. The question of ‘‘genes or behavior’’ makes
no more sense than the question of ‘‘behavior or energy
balance.’’ Consequently, although we might say that obesity has
a large genetic component to it, this doesn’t mean that the
obese have somehow miraculously deposited enormous quan-
tities of body fat without eating too much food, or expending
too little energy, or doing both.
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Facet one: trends in obesity over time
The prevalence of overweight and obesity in people has
increased dramatically in the last 30–50 y. For example, in
1980, 7% of the UK population was classified as obese. By 2000
this was 20%. Overweight subjects comprised ;20% of the UK
population in 1980. By 2000 this was 45%. Consequently, the
majority of current UK society is either obese or overweight (7).
The UK numbers are on the high side but are typical of many
European nations (1). In the U.S., the progression of obesity is
;3–4 y ahead of the problem in Europe; 2003 estimates suggest
that 31% of the population is obese (BMI . 30) (29).
Moreover, obesity has even greater prevalence in some
subpopulations. For example, the prevalence of obesity in
black populations across the entire U.S. is ;5% higher than in
colocalized white populations (30), and for black females,
FIGURE 1 The major causal linkages
among genetics, environmental effects,
physiology, behavior, and energy balance.
Multiple causal routes exist by which both
environmental and genetic effects may exert
their influence. The diagram clarifies that
behavior is not an alternative mechanism to
genetics, they are different levels of the same
phenomenon. Perceptions of energy imbal-
ance feed back into behavior and physiology
to influence both intake and expenditure. The
nature of these feedback links is disputed,
and they are omitted from the above frame-
work. The different feedback models are
addressed in Figure 2.
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
prevalence is even higher with ;50% obese. Socioeconomic
class and education also appear to be important factors, with
the lowest educated groups having ;5% higher prevalence
than more educated subpopulations (31,32). Similar demo-
graphic patterns are reported for almost all Westernized
societies. In addition, there are signs that this problem has
achieved a truly global distribution during the last decade;
many Asian, South American, and African nations report that
obesity rates are increasing rapidly (3–6,33).
It is easy to identify some correlated societal trends to the
obesity epidemic. One of the factors believed to be important is
television viewing (34–39). By the early 1970s, televisions were
already a virtually ubiquitous household feature in the U.S. and
most of Europe. What has changed is the amount of
programming. We now have a choice of many different
channels to watch 24 h/d: there is always something to catch
our attention and potentially keep us watching. By the late
1990s it was estimated that 20% of children in the U.S. were
watching .6 h of television every day. Parental ratings of how
much television a child watches are positively associated with
the child’s BMI (35), and having a television in a child’s
bedroom is a significant risk factor for obesity (37); also,
television viewing is negatively associated with engagement in
physical activity (38,40). However, significant differences
appear to exist in the associations within different ethnic
subpopulations, which suggest that the linkages are complex
(39). In adults, it was suggested that the association between
television viewing and BMI is stronger in women than in men
(36,41), but other studies have not reported this difference
(42).
Many other changes in activity patterns have occurred over
the last 50 y or so. In the 1950s most people in Western
societies walked around a range of small local shops to do the
week’s shopping. This has been almost completely replaced by
one-stop, out-of-town hypermarkets, where one can park
conveniently close to the store, buy everything in a large cart
that doesn’t have to be carried around, and then drive it all
home. There is no doubt that these changes were largely
facilitated by the spread of car ownership. Out-of-town
supermarkets could not have been a commercial proposition
in the 1950s, because only a small sector of the population
could have used them. Another factor in temperate zones
where it is cold in the wintertime is the work involved in
heating one’s home. The spread of central heating systems has
replaced the hard work that it took to keep coal fires burning.
The domestic appliance market has also made enormous
inroads into the labor that typified housework in the 1950s and
1960s. Washing machines, vacuum cleaners, dishwashers, spin
dryers, and tumble dryers have all reduced domestic work
chores. Our addiction to domestic appliances is such that we
now have devices that take any effort out of even the most
trivial of tasks, such as electric toothbrushes and carving
knives.
At the same time that there have been changes in activity
patterns, there have also been large changes in eating habits.
Key dietary behavior shifts include greater consumption of food
away from the home (43) and large increases in total energy
from salty snacks, soft drinks, and pizza (44,45). Despite these
changes, some studies suggest that total daily energy intake has
actually declined over the last 30 y (46,47), but other studies
suggest an increase (44), and yet others find no significant
trends (48,49). At national levels, however, food-sales statistics
show that for almost all food types, the same amount of food or
more is presently being purchased per individual compared with
20 y ago. This is particularly the case for confectionary items.
Over the last two decades, fat consumption has declined in
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parallel with the increased prevalence of obesity in both the
U.S. (50) and Europe (48), and the decline is matched by a
parallel increase in carbohydrate consumption (48,49).
It is clear that social changes involved activity reductions,
and this was potentially combined with an increase in energy
consumption. We should be cautious, however, about drawing
simple cause-and-effect arguments from these correlations with
the spread of obesity. For example, enrollments at health clubs
have also expanded over the same period that obesity has
increased. In addition, the stimulation of television and the
availability of cheap electric lighting means that on average,
individuals spend 2 h less each day asleep compared with the
1920s (51). Time spent sleeping is positively associated with
obesity (42), so this change should be protective. Despite these
caveats, some intervention studies have assessed the roles of
different factors. Studies in the U.S. were performed to try to
intervene in children’s television viewing habits to determine
the impact on body fatness. These interventions show a
significant effect on body weight. Surprisingly however, this was
not because the children adopted more active lifestyles when
deprived of their viewing time. Rather, the major differences
were in the consumption of snack foods: the children ate
these when watching television, but not when engaged in
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alternative pursuits (even sedentary ones).
Facet two: individual differences in susceptibility
The second facet of the obesity problem is that despite living
in similar environments, not everyone gets obese. This effect
can be traced to individual differences in behavior and
physiology. Millions of people eat regularly at burger bars, yet
others never visit them. In contrast, some people exercise
regularly, whereas others almost never do. Some of these
differences reflect substructuring of the environment in which
we live. For example, middle-class areas may have better
provision of parks and cycle paths, which encourage recrea-
tional activity. This is only part of the explanation, however,
because whatever environment or sector of the community is
chosen, it is populated by a mix of obese and lean people. One
explanation for these differences is that for everyone, there are
subtle differences in lifetime-accumulated experience and
social factors that lead to differences in behavior and
physiological energy expenditure. This experience may include
the period spent in utero. An alternative viewpoint is that these
behavioral differences have a large genetic component to them.
This model suggests that, when immersed in the same
environment, some people develop obesity because their
genetic constitution is such that they are more likely to adopt
behaviors or have physiologies (such as low RMRs) that lead
them into positive energy balance.
Calculations indicate that the heritability of BMI is high.
Accordingly, studies of monozygotic and dizygotic twins raised
apart and together and pairs of adopted and nonadopted
‘‘virtual twins’’ indicate the variation in body mass that is
explained by genetic factors is also very high. A meta-analysis
recently indicated that the average variation explained by
genetic factors was 77%, and that shared environmental factors
were insignificant (52). Faced with this information, it is
important to recognize what exactly is being said. A common
response to the suggestion that shared environments are
unimportant is to point out that if one were to take a pair of
twins and keep one of them locked up with minimal food for
years on end, the deprived twin would not develop the same
BMI as the twin given free access to food; hence it is ‘‘obvious’’
that environment must be important. However, although this
hypothetical experiment would probably yield the suggested
2094S SUPPLEMENT

result, such extreme environments are seldom encountered in

Western society. It appears that once certain environmental
requirements are met, additional variability in the environment
becomes relatively unimportant and genetic factors predomi-
nate. A counterexample to the starved-twin scenario clarifies
this point: if I had an enormous refrigerator in my house
continuously stocked full of food, it would probably have no
effect on my actual food intake if I were provided with a second,
similarly continuously stocked refrigerator. Once I have met
a certain minimal environmental requirement, additional
variation in the environment is irrelevant, and this appears to
be the present situation in Western society. Illustrating this
point further, the average income in the U.S. (in 2002 figures)
was $27,000 annually; yet it is possible to purchase one’s entire
daily energy requirements for ;$5/d (,5% of the average
annual income).
In this context, the changing prevalence of obesity over time
must be a gene-environment interaction effect. Addressing the
genetic side of this interaction is potentially a far more tractable
problem than addressing the environmental component by
reengineering society, because the level at which interventions
might ultimately be made is the individual rather than the
society as a whole. There is a clear need, therefore, to

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understand the genetic bases of food intake, energy expendi-
ture, and hence, energy-balance variations.

Regulation of energy balance

There is a generalized opinion that energy balance, and
hence, body weight and/or fatness, are phenomena that are
regulated (e.g., 53–57). The origins of this idea seem to reside
in calculations of the potential impacts of imbalances in our
energy intake and expenditure. For example, on average,
a typical candy bar contains ;250 kcal (1 MJ) of energy. If over
the last 23 y I had eaten a candy bar more than my energy
expenditure every day, I would have accumulated 23 3 365
3 1000 kJ 5 8395 MJ of extra energy. Because 1 kg of fat
tissue contains ;33 MJ of energy (58), the 8395 MJ would be
equivalent to deposition of ;254 kg of fat tissue! Even if I had
eaten a candy bar above my requirements only once each week,
I would have accumulated 36 kg of body fat. If such small
imbalances in our intake and expenditure can have such major
impacts on body weight, the argument is that these phenomena
normally must be regulated in some manner. However, this
calculation involves several dubious assumptions. It is assumed
that all of the excess energy is deposited as fat, and that the
deposited fat tissue expends no energy. More realistic
assumptions about the nature of the deposited tissue and the
energy expenditure of that tissue lead to the conclusion that
trivial imbalances in our energy balance generally lead to trivial
changes in our body weight (see, for example, 59–61).
Development of obesity actually requires quite severe im-
balances in one’s energy budget. Nevertheless, despite the
widespread acceptance that the trivial-imbalance argument is
wrong, it is still widely believed that energy balance, energy
intake, and body weight are regulated phenomena. This is
certainly not an outdated concept. A search on the ISI Web of
Science bibliographic database (Sept. 2003) on the term ‘‘body
weight regulation’’ revealed 432 articles with this phrase in the
title or abstract published between 1981 and 2003, of which 61
(14%) were published in the first 9 mo of 2003 (3.4% of the
total time).
Several different models are available for the manner in
which energy balance may be regulated (Fig. 2). In the simplest
model (Fig 2A), daily food intake and daily energy expenditure
vary as independent stochastically variable traits. The differ-
FIGURE 2 Three alternative models of energy-balance regulation
involve feedback from energy imbalance into energy intake and
expenditure. In one model, food intake and energy expenditure are
stochastically variable from day to day and independent of each other (A).
The resultant variations in energy balance translate into storage of lean
and fat tissue controlled by the p ratio. Lean and fat tissue also directly
affect the levels of energy expenditure. In the second model, there is
memory of the historical energy balance that feeds back onto food intake
and energy expenditure (B). If an animal spends a period in energy deficit
under this model, it will feed back an impetus to increase intake and
reduce expenditure. Alternatively overconsumption will lead to converse
feedback, reduced intake, and increased expenditure. In the third model,
the same feedbacks relative to historical energy balance come from the
fat and lean tissue reserves rather than historical memory (C).
ence between the intake and expenditure generates a daily
energy storage term that is either positive or negative de-
pending on the contributing factors. If the storage is positive,
energy is deposited; if the term is negative, energy is withdrawn
(61,62). The subject withdraws or deposits energy into or from
either stored fat or lean tissue depending on a utilization ratio
that is generally called the p ratio (59). All tissue expends
energy, but the rate of energy expenditure in lean tissue greatly
exceeds that in fat tissue. If there is an energy surplus, the
growth of the lean and fat tissues increases energy expenditure.
A sustained energy surplus will therefore result in sustained
growth of both lean and fat reserves until the expenditure
balances the intake. The differential energy expenditure of lean
and fat tissue, however, means that the amount of fat that is
deposited before the subject regains energy balance depends
critically on the p ratio. If this ratio is low, which reflects
diversion of energy into lean tissue, stability is regained at a
lower body fatness than if the p ratio is high. The key question
with respect to this model is whether the p ratio is an
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
individually defined parameter under genetic control or
whether it is instead variable and itself dependent on body
composition such that when subjects have large fat reserves,
they preferentially mobilize and deposit fat, but during periods
of negative energy balance, they reduce the p ratio and start to
mobilize protein as well and thus autoregulate (to some extent)
their body composition (60). Several arguments suggest it is
unlikely that the p ratio is individually fixed (63).
The p-ratio model can explain many features of energy
balance without the need to invoke any regulatory signals
generated by lean or fat tissues, particularly if the p ratio is
fixed genetically (59). The model, however, is an inadequate
description of phenomena related to energy regulation (60–
63). The main difficulty faced when using this model is
explaining patterns of intake that occur after periods of food
deprivation. During food deprivation, subjects tend to reduce
their expenditure more than can be accounted for by the loss
of metabolizing tissue (64–66). On refeeding, they also tend to
exhibit post-restriction hyperphagia. These patterns would not
emerge if intake and expenditure were independent stochastic
variables linked only to storage by the p ratio. The salient issue
is this: When we have been food deprived, where do the
feelings of hunger come from that cause us to subsequently
overeat and reduce our energy expenditures to redress the
previous energy imbalance? Two basic possibilities exist. First,
there may be a sensing mechanism that monitors the extent of
energy imbalance by the fluxes of nutrients related to intake
and expenditure. The ‘‘glucostatic’’ model of food intake
regulation (67) is this type of energy balance–regulation
model. By this hypothesis, feeding behavior is regulated by
fluctuations in circulating levels of glucose, which are sensitive
to patterns of both energy expenditure and intake. Thus if
glucose-sensing centers in the brain detect a drop in
circulating glucose levels, feeding is stimulated, and feeding
is then terminated by the increase in circulating glucose.
Glucose status, therefore, acts as a sensor for immediate energy
balance. This is, however, a signal that monitors only the
short-term flux of energy. It is likely that animals, including
humans, have also evolved mechanisms to monitor patterns of
energy imbalance over much more protracted periods. This
could be an accumulated memory of energy balance (Fig. 2B)
or, an alternative source of such signals is the energy stores
themselves.
The third class of model therefore invokes a feedback loop
(Fig. 2C) generated from the stored energy (fat and lean tissue
stores) (61,68–70). This could work in several different ways,
but two models predominate. One mechanism is that energy
intake and expenditure rates are tied into the sizes of the energy
stores by an amplification mechanism (71). When stores are
large, the signals from the stores do not stimulate feeding very
much but have a strong effect on expenditure. Conversely,
when the stores get smaller, the effect on expenditure is
diminished and the effect on feeding is increased. The second
way this might operate is by reference to a target store size that
is encoded centrally (72–75). Because most energy is stored as
fat, the suggestion is that the regulated body component is body
fatness (with lean body mass dragged along by some unknown
mechanism in the p ratio). Other models are also feasible where
lean mass is directly regulated (68). The regulation of body
fatness by reference to a centrally encoded target is generally
attributed to Kennedy (69) and is called the ‘‘lipostatic’’ model
of body weight regulation.
At present, the exact nature of the regulatory model for
energy balance and body weight remains uncertain, and
separating the alternatives models is not easy. In particular,
the feedback from an accumulated memory of the status of
2095S
energy balance (model 2) and feedback from the stored reserves
(model 3) might be difficult to resolve. This is because in most
circumstances, the two factors move in parallel. It is seldom the
case that someone could accumulate an energy deficit but not
affect levels of their stores and vice versa. To test between these
models, therefore, requires an experimental design that
separates the different effects. If the system works as envisaged
in model 2 (Fig. 2B), with a memory of energy deficit feeding
back to drive intake and expenditure, then it seems likely that
this memory will decay over time. For example, if I starved you
for 24 h, you would feel hungry the next day. If I gave you free
access to food the day after you had starved, you would overeat
to compensate for the missing intake. However, if I stopped you
from overeating for a week after your starvation day, but gave
you enough to balance your energy demands, and then gave
you free access to food, you would probably not feel as hungry as
you did the day after you had starved. This is because
the memory of the energy deficit had receded because of the
intervening time spent in energy balance. This decline in the
force of memories of energy deficit over time could be used to
separate regulation by model 2 from model 3 (Fig. 2C). The
design is as follows: a set of subjects is placed on an energy-
restricted diet that provides fewer calories in food than they
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were expending with a resultant loss of body weight (fat and
lean tissue). At the same time, they accumulate memory of
energy deficit. After a suitable period on restriction (of say,
3 mo), the subjects are randomized into one of two groups. Group
1 is taken off the diet immediately and given free access to food.
Group 2 is fed enough food to keep the body mass constant and
is regulated on a daily basis for an additional intervention
period of 3 mo and is then given free access to food. At the end
of this period, group 2 will have the same body fat and lean
stores as group 1, but will have been fed in energy balance for
3 mo. Hence, if it is the size of the stores that drives the
hyperphagic responses, the extent of hyperphagia in the release
phase of the experiments will be the same for the two groups.
In contrast, if it is the memory of energy deficit that drives
the hyperphagic response, group 1 will have a much stronger
hyperphagia than group 2, because the memory of deficit
will have receded over the 3 mo that group 2 was fed in energy
balance. In general, the more time spent feeding in energy
balance, the lower will be the predicted hyperphagic
response.
These experiments have not yet been performed, but would
be extremely informative. It seems likely that elements of all
three different models are important. First, short-term signals
probably play a critical role in switching feeding behavior on
and off and in regulating short-term activity patterns. The p
ratio is an important aspect of nutrient allocation that governs
how energy surpluses and deficits are translated into body
composition, whereas long-term signals that potentially interact
with centrally encoded targets provide an overall orchestration
of the short-term regulation mechanisms.
There is some experimental support for this regulatory
framework. Many studies show that when subjects are food
deprived, they compensate for the deprivation by reducing their
energy expenditure. Although less frequently performed, the
converse, increasing expenditure in response to overfeeding, is
also observed (e.g., 76,77). Perhaps the most comprehensive
study was that of Leibel et al. (78), who placed obese and lean
subjects in a protocol where they were systematically under- or
overfed to produce differences in their body weights by ;10%.
The researchers then examined the compensatory responses in
the subjects’ energy-expenditure patterns. As anticipated by
the model, when subjects were underfed, they responded to the
energy deficit by decreasing their expenditure more than could
2096S SUPPLEMENT
be accounted for by the mass change, whereas under conditions
of energy surplus during the overfeeding part of the study, they
responded by elevating their energy expenditure. The con-
tributions of changes in RMR and nonresting energy expendi-
ture to these compensations were about equal. In other studies,
differential responses to overfeeding are reported: some
individuals gained body weight whereas others did not. The
extent of the weight gain was dependent on the extent to which
the subjects performed spontaneous activities to burn off the
excess energy (79–81).
During the 1950s at about the same time that ideas were
evolving about lipostatic, proteostatic, and glucostatic
mechanisms of energy regulation, a spontaneous mutant mouse
occurred at The Jackson Laboratory in the U.S. This mouse,
which became excessively fat, was called the ob/ob mouse,
because it was clear that the original mutation was a single-gene
recessive defect that caused its (ob)esity. When heterozygous
ob/1 mice breed together, one quarter of the offspring are
homozygous ob/ob mutants, and they feed voraciously relative
to their littermates. They also have reduced metabolic rates and
lower body temperatures, and as they get older, they become
less active. In combination, this leads to a dramatic energy
imbalance, and the mice become very obese. On average, by 12
wk of age, they weigh almost twice as much as their
heterozygous and wild-type littermates. Since that time, many
other natural, mutant, fat mice and rats have been developed
and bred by the major mouse- and rat-breeding companies such
as the db/db diabetic mouse, the fa/fa fat rat, and the tub/tub
tubby mouse.
A series of elegant parabiosis experiments with ob/ob and db/
db mice were performed to try to elucidate the nature of the
genetic defects that these mice harbor (82,83). Parabiosis
involves surgically joining the blood circulation of pairs of mice
with the result that any circulating factor in the blood of one
animal is passed to the other and vice versa. When the fat ob/ob
mouse was joined together in parabiosis with a lean wild-type
mouse (1/1), the ob/ob mouse started to eat less food and to
lose body weight. However, when a fat db/db mouse was joined
in parabiosis to a wild-type 1/1 mouse, something radically
different happened. The db/db mouse was unaffected, but the
wild-type mouse started to eat less food and eventually died of
starvation. Joining together ob/ob and db/db mice had a similar
result to joining up ob/ob to 1/1 mice: the ob/ob mouse
reduced its food intake and started to lose weight, but the db/db
mouse continued to eat and remained fat.
These experiments provided strong support for the lipostatic
model (69). It was clear that the ob/ob mice have a defect in the
signal that tells them how fat they are. In the absence of this
signal, the mice ‘‘think’’ that they are dangerously thin relative
to their target, and they therefore elevate their food intake and
suppress their metabolism and body temperature so that their
body weight increases to meet the target. In parabiosis with
wild-type mice, ob/ob mice start to get a signal from the fat in
the lean mouse’s body, and they suppress their food intake and
normalize their body temperatures. Because this also happens
when ob/ob mice are in parabiosis with db/db mice, the db/db
mutation cannot also be a problem with the signal. The
mutation in db/db mice must actually be a problem with reading
the signal in the brain. Hence, the db/db mice also ‘‘think’’ that
they are dangerously thin, and effect changes in their food
intake and expenditure to bring their fatness up to target.
When db/db mice are placed in parabiosis with wild-type mice,
there is no effect on their food intake, because they are already
producing lots of the signaling factor (it just isn’t being read), so
getting more of a signal from the wild-type mouse has no effect.
However, for the wild-type mouse the situation is more serious,
because in parabiosis with a db/db mouse, a wild-type mouse
receives a massive signal from the db/db animal; ‘‘thinking’’ it is
massively over its target, the wild-type mouse shuts down its
food intake to try to lose weight. Because the db/db partner
keeps eating, however, there is always a signal telling the wild-
type mouse not to eat, and eventually it dies of starvation.
Despite these insights, it was another 20 y before the signaling
compound was finally identified. The mutation causing the ob/
ob mouse signal was a single-base mutation in a gene located on
chromosome 6 (84) (mapped to chromosome 7 in humans).
The consequence of this mutation was that instead of the gene
signaling the production of a full-length 167–amino acid
protein, the presence of a premature stop codon caused a much
shorter, nonfunctional protein to be produced. The signal
protein was called leptin from the Greek root leptos, which
means thin, because the animals that had full-length leptin
were lean.
In the seminal paper on leptin (84), it was shown that leptin
is produced exclusively in adipose tissue, which is as one might
anticipate for a compound that acts as a lipostatic signal of the
size of body fat stores. Subsequent work shows other sites of
production at much lower levels in developing fetuses, placenta
(85–88), and stomach (89). When recombinant leptin was
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injected into ob/ob mice, the animals ate less food and
dramatically declined in body weight (90–95). Other features
of the genetic pathology were also normalized, including for
example, the ability to sexually mature and breed (96).
Moreover, in wild-type mice, exogenous leptin also reduced
the animals’ body weight, as one might anticipate if the mice
received an erroneous signal about the size of their body fat
stores (90–92). In mice with targeted transgenic overexpression
of leptin production, there is a dramatic decrease in body
fatness (97).
The leptin receptor (Ob-R) is a cytokine receptor (98) with
several splice-variant forms including a short form (Ob-Ra) and
a long form (Ob-Rb). The long form of the leptin receptor
contains an intracellular signaling domain that is missing from
Ob-Ra. The dominant intracellular signaling mechanism
appears to act via the Janus kinase/signal transduction and
activation of transcription pathway (99). Leptin binding (100)
and receptor–localization studies revealed that Ob-Ra is found
in the choroid plexus (101), and Ob-Rb is expressed in large
quantities in several nuclei of the hypothalamus, particularly the
arcuate nucleus (ARC) (102,103), and also in the brain stem
(104). The location of the signaling form of the leptin receptor in
the hypothalamus was significant, because early brain-lesioning
studies on rodents showed that removing segments of the
hypothalamus has a profound effect on several motivational
processes including feeding behavior. It is now known that two
types of neurons in the ARC receive the peripheral leptin signal
(102–105). One type known as neuropeptide Y/Agouti-related
protein (NPY/AgRP) neurons coexpress NPY, and AgRP (106)
have projections that can be traced into the brain stem to the
paraventricular (PVN) nucleus and to the second type of cell
that receives the leptin signal in the ARC. The second type of
neurons is called pro-opiomelanocortin/cocaine amphetamine–
regulated transcript (POMC/CART) neurons (107,108).
POMC/CART neurons also receive projections from neurons
in other brain areas that express serotonin (5-HT) and have
5-HT receptors on their surfaces.
Both POMC/CART and NPY/AgRP neurons project to cells
in the PVN that express melanocortin-4 receptors (MC4-R)
and also to cells in the ventromedial nucleus that express
melanocortin-3 receptors (MC3-R). Both of these mel-
anocortin receptors are G protein–coupled receptors. POMC/
CART neurons secrete a-melanocyte–stimulating hormone
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
(a-MSH), whereas NPY/AgRP neurons secrete AgRP. a-MSH
is an agonist, and AgRP is an antagonist of both MC4-R and
MC3-R (109). When leptin molecules from the periphery dock
with their receptors on NPY/AgRP neurons in the ARC, there
is suppression of NPY release (110,111) and reduction in
g-aminobutyric acid (GABA) release at the synapses where the
NPY/AgRP neurons meet the POMC/CART neurons. Under
the GABA-mediated disinhibition and combined with direct
leptin stimulation, the POMC/CART neurons release a-MSH
at the MC4-R on PVN neurons at the same time that the
antagonist AgRP derived from the leptin-stimulated NPY/
AgRP neurons is reduced. Secretion of a-MSH depends on
successful cleavage of the POMC molecules, which is brought
about by the proconvertase-1 enzyme. Additionally, the
stimulatory effect of a-MSH appears to depend critically on
its acetylation status, which is also under regulatory control of
acetylase-deacetylase enzymes. The increased a-MSH and
reduced AgRP levels stimulate the MC4-R with two down-
stream effects. First, the sympathetic system is stimulated and
releases noradrenaline at peripheral cells that express b-adren-
rgic receptors. In brown adipose tissue in rodents, this produces
an immediate stimulation of metabolic rate. At the same time,
food intake is inhibited. The resultant negative energy balance
causes leptin levels to decrease. This reduced signal has the
opposite effects in the ARC nucleus: NPY/AgRP cells are
stimulated to release NPY; POMC/CART cells are inhibited
(directly and indirectly), and at the MC4-R in the PVN, AgRP
release is enhanced, whereas a-MSH level is reduced. This
leads to reduced sympathetic activity, reduced energy expen-
diture, and stimulated feeding behavior.
There is now considerable evidence that the leptin system
interplays with other signals that may also be involved in long-
and short-term regulation. The best-characterized of these so
far is insulin. Like leptin, the secretion of insulin is proportional
to the magnitude of the body fat stores. Neurons in the ARC
that express the leptin receptor also often express the insulin
receptor IR-1. The insulin receptor signals via the
phosphoinositide 3-kinase pathway, and there is suggestion
(112) that intracellular interaction between leptin signaling
and insulin signaling may exist. Insulin is known to inhibit NPY
(113), and animals with reduced numbers of insulin receptors
have elevated food intake consistent with increased NPY levels
(114). Insulin may act as a long- and short-term signal given its
responsivity to altered glucose levels after feeding. Similar
short-term signals include glucose and free-fatty acids them-
selves and peptides secreted from the gut such as cholecysto-
kinin (115), ghrelin (116), and peptide YY (PYY,117),
receptors for which also colocalize to ARC cells.
The situation in humans is likely to be more complex than in
rodents because of the input of cortical-level processes (118).
Moreover, we are aware that endogenous cannabinoids and the
serotonergic and opioid-dopaminergic (119) systems are also
involved, but the details of the interactions presently remain
obscure. Nevertheless, this model potentially explains why
many people are able to regulate their body weight over periods
of many years. Whenever one puts on too much weight, leptin,
insulin, and probably other signals are generated that reduce
food intake and increase energy expenditure until the signals
and weight are normalized. Whenever one loses weight, the
opposite occurs: the multiple signals decrease in magnitude,
food intake is stimulated, and energy expenditure is suppressed
to regain the missing weight.
One major argument against the lipostatic theory of weight
control is the fact that so many people are presently obese. If
such a system operates, the argument goes, then clearly it
cannot be very effective. However, even if lipostats exist,
2097S
obesity may develop for two reasons. First, obese people may
have broken lipostats; or second, the lipostats in obese people
may be set at very high target levels. After the discovery of
leptin, there was immediate interest in whether obesity was
a result of deficient leptin production—a broken lipostat.
Obese people might have abnormalities in their ability to
produce leptin in much the same way as the leptin-deficient ob/
ob mouse. Imagine, for example, if my leptin production was
only half of the normal rate. My brain would think that I was
only half as fat as I actually am, and it would encourage me to
eat more food and expend less energy until my fat content was
high enough to redress the leptin-production deficiency. If this
were the case, the potential to cure obesity would be in sight:
one could treat people with leptin (or drugs to mimic its action
or stimulate natural leptin production) to trick the brain into
thinking that one was fatter than was actually the case. The
regulatory system would then downregulate food intake and
increase energy expenditure to redress the balance. The only
downside is that this would need to be a lifelong treatment,
because discontinuation would lead to decreased leptin levels
and resultant weight regain. However, the euphoria over the
potential of leptin was short lived, because it was found (120–
124) that in general, fat people have very high leptin
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concentrations, as might be expected from their high body
fatness if their leptin-production systems were working
correctly. The vast majority of obese people do not have
leptin-production deficiencies or defects in their leptin re-
ceptors (125).
An interesting exception was two children from Cambridge,
UK (126). These children were ,10 y old when they were
discovered, but they already had ravenous, insatiable appetites.
This had resulted in extreme obesity that had forced their
parents to seek hospital treatment for them. These children
were massively obese; for example, the older child, when aged
10 y, weighed 110 kg. Both children had no detectable levels of
circulating leptin in their blood. Additional investigations
showed they had a recessive mutation in their leptin gene that
prevented leptin production. Once the defect was diagnosed,
the children were treated with recombinant leptin. With daily
injections, their dramatic weight-gain trajectories and compul-
sive-eating behavior were reversed (127). Since this time, other
families have also been described with leptin-production
deficiencies including a family of three people from Turkey
whose body weights almost halved when they received daily
leptin injections for 10 mo.
An interesting subpopulation of the obese are individuals
that are heterozygous for the leptin deficiency. These in-
dividuals have lowered leptin production for their body fatness
levels, and as a consequence they are on average more obese
than their homozygous wild-type relatives (128). These
heterozygous individuals are also extremely rare but provide
an important proof of principle regarding the functioning of the
lipostatic control mechanism. Some individuals have been
identified with loss-of-function mutations for the leptin
receptor Ob-Rb. A small group of individuals has also been
identified with mutations in the POMC gene, which makes
them unable to secrete a-MSH (129,130). Because these
subjects do not secrete a-MSH onto the MC4-R in the PVN,
they have a perpetually stimulated appetite and develop
obesity. A second consequence of this mutation is the subjects
have bright-red hair (130) because of an absence of a-MSH
interacting on MC1-R in the periphery (131). However, the
most important single-gene defects of which we are presently
aware concern polymorphisms of the MC4-R itself (132–134).
Many polymorphisms have been identified in this gene (135)
most of which do not have any functional significance (136).
2098S SUPPLEMENT
Some key polymorphisms of MC4-R are associated with obesity,
and in most populations that have been studied to date,
mutations of this gene account for ;3–5% of all morbid obesity
(133).
Overall then, completely broken lipostats explain only
a small portion of the total numbers of obese and overweight
people. What about the genetic ‘‘mis-setting’’ of lipostats at
high targets, which then interact with the environment to
generate the temporal and spatial patterns of susceptibility that
we presently observe? Is this a feasible alternative explanation
for the high prevalence of obesity? The negative-feedback
model of body weight regulation has many similarities with
thermostatic temperature regulation in a house (137). In that
system, a room-temperature sensor compares the actual and
desired room temperatures, and an effector system (the
radiators) can be modulated to bring actual and desired states
into balance. We can understand the interplay between genes
and the environment by using this thermostatically heated–
house analogy. Imagine houses have a whole range of
thermostatic temperature set points from cold to hot. If the
houses were all in the arctic and were poorly insulated, then all
the house temperatures would be cold because even those with
high set points (or broken thermostats) couldn’t get as hot as
their thermostats want them to be because the capacity of their
heating systems wouldn’t be able to match the heat loss
through their roofs. This is equivalent to the genetic system
being environmentally constrained. However, if the houses
were all in the tropics, where the environmental temperature is
much warmer, then those with high target temperatures (or
broken systems) would reach their high temperatures. This is
equivalent to the genetic system being released from environ-
mental constraint.
The key point is that actual house temperatures depend on
both the thermostat characteristics and the environment in
which the houses are located. Our genes may predispose us to
obesity, but genes can only be expressed in environments, and
it is the gene-environment interaction that is most important.
Obese people might have high target body fatness settings in
their lipostats that result in actual high body fatness in Western
societies where there is ready access to high energy–content
foods. Presently in rural, primitive farming communities, and in
the past in Western societies, people might have (or have had)
high target settings or breakage in their regulation systems.
However, if they had to work 12 h/d digging fields or chasing
prey, they may have been unable to ever consume sufficient
food to reach this target.
Evolutionary context
One difficulty with this interpretation is understanding the
evolutionary processes that might result in systems evolving
with such variable individual lipostat settings. Our knowledge
about the evolution of body-weight–regulation mechanisms in
humans is poor. Generally, arguments tend to paint simplistic
adaptive scenarios emphasizing that storing large amounts of fat
might at some point have been selectively advantageous (e.g.,
because it would provide increased resistance to starvation) the
so-called thrifty gene hypothesis. The main problem with such
‘‘adaptive’’ scenarios, however, is understanding why such an
advantageous genotype would not rapidly replace the dis-
advantageous ‘‘non-thrifty’’ genotype, and make everyone in
modern society susceptible to obesity. This problem is seldom
recognized in such adaptive landscapes.
Studies of wild animals suggest that stored body fat is
actually regulated under stabilizing selection as part of a dynamic
tradeoff between the risks of starvation, which promote fat
storage, and the risks of predation, which promote leanness
(138–147). Because early humans likely also faced these
contrasting selective pressures, they probably also evolved
a regulatory system (i.e., a lipostatic system) that promotes fat
storage to avoid starvation but also prevents excessive fat
storage to avoid predation (148). The set point of this system
may have been temporally variable because of the differing
selective pressures at different times of year. Several key events
in human evolution likely have dramatically reduced the risks
of predation. These include the evolution of social behavior,
which allows groups of humans to drive away predators and
alert each other of the presence of danger. Such behaviors are
also observed in modern-day groups of apes and monkeys such
as vervet monkeys, which have evolved complex signals to
indicate the approach of different types of predators (149–152).
The harnessing of fire ;1.8 million y ago (153) and the
construction of tools to actively aid defense would further
enhance protection against the threat of predation. Under this
release from constraint, it is feasible to imagine that target set
points might drift upward at random because they would have
no selective consequences as long as actual body weights were
constrained by food supply. This would remove the strong
selection that imposed an upper limit on fat storage, but defense
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against energy deficits would still be strongly selected for. This
asymmetry accords with modern experience (154). In this
evolutionary scenario, the capacity to deposit enormous fat
stores is not seen as adaptive; hence there is no need to explain
why the trait did not spread through the entire population.
Several hundred generations later, when faced with the
Western lifestyle, the continued absence of strong selection
on the lipostat target would result in a diversity of targets and
the consequent diversity of body-fatness phenotypes that we
presently observe. One additional prediction from this
hypothesis is that the greatest release from the constraints at
the upper boundary of regulation should occur in those
populations that have been most liberated from the risks of
predation. There is no lower risk than living in a completely
predator-free environment, and although such environments
are uncommon, small remote islands generally have no
predators that are likely to pose a risk to humans. It is perhaps
significant that the greatest levels of obesity in modern
populations occur in Pacific Islanders, where some islands have
.70% of people in the obese category (e.g., Tonga; 155).
Why conventional behavioral (energy restriction)
approaches to weight loss don’t work
The most-common treatment prescribed for obesity and
overweight is to engage in an energy-restricted diet. Indeed in
many countries, before obese subjects can be prescribed drugs
to assist them, they need to have tried this option first.
Moreover, this is a method of choice for attempting to reduce
weight by overweight subjects (and people in the normal weight
range). Recent surveys suggest that at any one time, 40% of
people in Western societies may be engaged in some form of
energy restriction. Vast numbers of options are open to people,
and a large dieting industry caters to these needs. Many
organized ‘‘dieting clubs’’ promote calorie restriction as the
method of choice for regaining control of body weight.
Unfortunately, almost all of these approaches provide the
promise of short-term success coupled with long-term failure.
If one consumes a low calorie–intake diet that provides less
energy than one expends, the result is reduced energy storage
that is manifested as a loss of body tissue, some of which is fat
and some of which is lean, depending on one’s p ratio, which
varies with how fat one already is and perhaps also the rate of
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
weight loss. Whatever is claimed to be the mechanism, all
successful weight-reduction diets work on the principle of
energy deficit. The major differences between diets are the
effects that they have on our short-term perceptions of hunger
and their side effects on other systems. Presently, popular diets
such as the Atkins diet rely on large quantities of dietary
protein almost to the exclusion of carbohydrate. The scientific
basis for this diet is that there appears to be a hierarchy of
macronutrient effects on perceptions of hunger: fat is least
satisfying, carbohydrates next, and finally, the most satiating
macronutrient is protein (156). A diet that provides an energy
deficit, where most of the calories come from protein, therefore
leaves one feeling less hungry than if the same deficit came from
a fiber-dominated diet. But weight loss is the same for the same
energy deficit. The difference is that because perceptions of
hunger are different, it may be easier to adhere to a high-
protein diet than a high-fiber diet, and the longer one stays on
a diet, the more weight is lost.
Potentially major problems exist with high-protein/low-
carbohydrate diets. First, these diets are generally deficient in
micronutrients (which can be rectified by taking a vitamin
supplement) and also, possibly, in carbohydrates that are
important for optimal function of the central nervous system.
Second, a high protein intake is generally coupled with a high
saturated fat intake and a high serum cholesterol level, both of
which are implicated as causal factors in cardiovascular disease,
cancer, and stroke independent of the obesity they engender.
Urinary calcium excretion increases with high protein intake.
Moreover, bowel cancer is strongly negatively correlated with
dietary fiber content, and so excluding fiber from the diet
enhances the risk of developing bowel cancer. Processing high
protein loads may also increase the risk of kidney failure
because of the concomitant high rate of urea production.
These high-protein/low-carbohydrate diets are consequently
only appropriate for the short term. Even then, the benefits of
weight loss need to be balanced against the negative side
effects. During 2001, the American Heart Association and the
World Cancer Research Fund both came down heavily against
these diets as aids in the fight against obesity. A meta-analysis
of high-protein diet interventions and their effects concluded
that high-protein diets do result in greater weight loss than
conventional diets, but that one of the largest potential
problems they pose is increased calcium excretion in urine,
which may ultimately contribute to excess bone loss (157).
The most beguiling aspect of all energy-controlled diets is
that in the short term, they do result in significant weight loss. If
one is in caloric deficit, then one’s feedback mechanisms
respond by attempting to minimize the magnitude of the
difference between what is being eaten and what the body
requires. One becomes lethargic, and activity level and resting
metabolic rate are reduced (78). Consequently the rate of
weight loss slows as the time under restriction progresses, and
eventually a steady state is reached where the reduced intake is
matched by reduced energy expenditure. To sustain additional
weight loss requires an even more stringent reduction in energy
intake. The weight that has been lost is maintained only with
sustained dietary control.
The only way to permanently lose weight on a diet is to stay
permanently on the diet or replace it with some alternative
form of caloric intervention like exercise (158). This is because
once the diet is stopped, body fat content is considerably lower
than the body’s target fatness; the body produces low levels of
leptin and other signals to indicate it is ‘‘under target.’’ The
major impetus of the lipostatic regulation system is to redress
this imbalance by impelling the individual to eat more food. To
emphasize this, it is noteworthy that an almost 100% successful,
2099S
permanent treatment for obesity is surgical intervention such as
gastric banding. This works because it forces people to comply
with calorie restriction forever.
We can understand why calorie-restricted diets don’t work
for weight control by reconsidering the analogy of the thermostat
in a house (137). Imagine your thermostat is set very high and
your house is hot. You aren’t happy with this situation, but
because you don’t know how the thermostat works, you call in an
‘‘expert’’ who opens the sitting-room window. There is an
immediate improvement in the house temperature. Over the
next few days, the house cools to a more comfortable level, but it
is still a bit too warm; you need to open another window to keep
the temperature decreasing. Eventually you reach a desirable
temperature. Somebody comes by and says that you might have
exposed yourself to some risks by opening your windows like
that: your kids might get colds in the drafts, and you might get
burgled. You decide after a while that having the windows open
is not a great idea, and you close them. Immediately the
temperature starts to rise again, and soon you are back to your
boiling-hot house. Energy-restriction diets are like attempts to
fix your house temperature by opening a few windows. They are
effective, but they only work as long as you stay on them, and
they sometimes have undesirable side effects. Usually, dis-
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continuing the diet results in you regaining the original weight
(159). In fact, the diet food–products industry is a multibillion-
dollar enterprise because diets work in the short term, but the
population of potential customers is never seriously diminished
by the diets themselves.
Alternative approaches: working with the lipostat
rather than against it
If leptin works in leptin-deficient subjects (127), then could
it be used in other obese people to trick their brains into
thinking they are even fatter than they are? After all, leptin
administration to mice that had no genetic problems in
producing leptin caused weight loss (91), and individuals that
are heterozygous for the loss-of-function mutation respond as
expected from their lower leptin levels (128). Moreover,
transgenic mice overexpressing leptin almost completely lose
their body fat (97), and appetite loss in subjects at high altitude
appears to be linked to elevated leptin concentrations (160).
Clinical trials with leptin started in the late 1990s. The largest
trial (161) included ;75 obese patients who were given daily
leptin injections as different doses. The subjects were also
prescribed a diet that over the 6-mo study period was expected
to result in weight loss of ;12 kg. The study revealed that
subjects on placebo treatment lost on average only 1.4 kg,
whereas those on the highest doses of leptin (0.3 mg/kg) lost
five times as much (7.1 kg). Although this modest weight loss is
lower than anticipated (12 kg) given the prescribed diet, it is
clear that the people on leptin treatment found it easier to
adhere to the dietary prescription. The major problem,
however, is the dose of leptin required to obtain this result
involved an injection of ;30 mg of leptin each day (161). With
the present (2004) price of recombinant leptin of approximately
$100/mg, this treatment would cost $3,000/d. This is unlikely
to be the sort of treatment that could be envisaged for large
numbers of patients in general therapy, because it would cost
more than treating the health consequences of the obesity. In
addition, ;15% of the patients on the trial receiving leptin
exhibited moderate to severe allergic reactions at the injection
sites.
Although leptin has not provided the solution it once
promised, it does provide some reassurance that the system in
humans is not radically different to that in rodents. Using
2100S SUPPLEMENT
animal models, therefore, is the best hope we have of finding
general solutions to the obesity problem. If leptin production is
not the problem, then other possibilities are that the leptin fails
to cross the blood-brain barrier (162) or the signal is not read
properly by the receptor system (both contributing to so-called
leptin resistance). In the last couple of years, there has been
enormous interest in other signals from the periphery that may
play a role in signaling energy status to the brain and may
therefore be putative targets for drug development. The two
major ones are ghrelin, which is a growth hormone secreta-
gogue produced by the stomach, and PYY3-36, which is also
a gut-derived signaling compound. The effects of these
compounds remain controversial, and a vigorous debate is
presently occurring over their effects on body-weight control.
The future
Although we have seen spectacular advances in our
understanding of the molecular basis of body-weight regulation
during the decade since the discovery of leptin, and within the
next decade we are likely to see drugs on the market that work
with this system rather than against it to produce weight loss,
there is still a great deal that we do not understand. Three
sources of information serve to quantify the extent of our
present ignorance about the control system and its interrela-
tionship with obesity, as follows: 1) genetic mapping studies,
which identify the specific regions of the genome where
polymorphic loci are associated with variation in body weight;
2) actions of drugs that produce effects on body weight for
which the mechanism is unclear including drugs that have
weight gain as an unexpected side effect; and 3) examination of
the lipostatic model itself, so we can see areas where our
understanding is deficient.
Genetic mapping studies aim to identify quantitative trait
loci (QTL) where important genes are located that influence
body weight. QTL mapping involves studying the genomes of
families where there is divergence in the BMIs of the two
parents. When such individuals produce offspring, these
children inherit half their genetic material from their father
and half from their mother. Each of these contributions is
a mixture of the DNA that the parents inherited from their
parents. By using genetic markers along the genome, it is
possible to trace which bits of chromosome have been inherited
by which children and associate this with the development of
obesity in those children. Across many such pedigrees, it is
possible to identify regions of the genome where variations
generate variability in BMI. These regions are known as QTL.
Chagnon et al. (163) summarized the QTL-mapping studies
performed to date and identified 68 different QTL regions of
the human genome where significant associations were found
between body fatness (normally BMI) and polymorphic
variation. These are spread across all chromosomes except
the Y chromosome. Seven of these loci were confirmed in
multiple (between two and five) studies. Interestingly, few of
these map closely to candidate genes for compounds presently
known to be component parts of the lipostatic system. That we
do not know the candidate genes at these major loci is a strong
message that our understanding of this system and the manner
in which it works is still rather rudimentary.
The second line of evidence concerning our ignorance
derives from drug effects on appetite and energy balance, and
that we do not fully understand how they work relative to the
lipostat system. First, one of the two pharmaceuticals licensed
for the treatment of obesity falls into this class. Sibutramine is
a 5-HT–reuptake inhibitor that produces significant weight
loss. There is an indication that the actions of leptin and
serotonin interact (164), but as yet this is poorly understood.
Second, a phenomenon that is reported by marijuana users is
that smoking the drug stimulates appetite. The discovery of
endogenous cannabinoid receptors (CB-1), which are putative
drug targets, has led to the development of agonist and
antagonist drugs that bind to these receptors. There are already
CB-1 antagonist drugs that appear to generate significant
reductions in appetite and weight loss (165). The details of how
they work, however, beyond interacting with the CB-1
receptor, is unclear. Finally, there is a whole class of drugs
that have weight gain as a side effect of their use. These include
many of the antipsychotic treatments for schizophrenia such as
clozapine and olanzapine (166–168). Significant weight gain on
these drugs appears to include a combination of effects on
expenditure and intake (166). The drugs are known to be
active at many types of receptors in the brain including
histamine, dopamine, and 5-HT receptors (169). Their mode of
action relative to the established network downstream from
leptin is unclear.
If we consider the model of the lipostatic system, it is evident
that there are large blanks in our understanding of how this
system actually works. We know some of the signals that
emanate from the periphery to indicate energy status, but we
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don’t know how many other signals there might be and the
timescales over which they are important. How partitioning of
energy (the p ratio) is controlled also remains unclear. There
has been considerable debate about the nature of transport
processes for the peripheral signals across the blood-brain
barrier (162) and whether defects in these systems interfere
with efficient signaling, but little progress has been made along
these lines. Intracellular signaling once the main compounds
hit their target receptors has been actively studied, and
considerable progress has been made in understanding how
leptin and insulin modulate gene-expression profiles in their
target neurons. Initial events downstream from leptin are
starting to become clear. However, the interactions beyond the
MC4-R in neurons within the PVN are far less understood.
Generally published models have arrows that emerge from this
point to feeding behavior and energy expenditure, but the
detailed mechanics of how feeding behavior and expenditure
are controlled are vague. As our understanding of this area
blossoms, there will likely be a whole range of new targets to
which pharmaceutical intervention may be possible. In the
effector system, the molecular basis of variability in resting
metabolism (170) and the way that activity levels are regulated
remain virtually unknown.
One area that we still know very little about is the nature of
the encoding of the lipostatic target weight. Several small-
animal models appear to be particularly suitable for investigat-
ing this phenomenon including animals that alter their body
weight in response to changing seasons (171,172). We do know
that these changes are signaled by altered photoperiod: by
switching the photoperiod, it is possible to move animals from
one level of regulation to another. An example of such a switch
occurs in the bank vole Clethrionomys glareolus (173). When
bank voles maintained in cold conditions are exposed to a short
photoperiod, they have a low body mass and relatively little fat
storage. If the photoperiod is altered to yield a long day (16 h of
light), the animals put on weight for a period of ;2 wk until
they are ;10% heavier (Fig. 3A). Most of this weight gain is fat
tissue. They then reestablish control at this higher level. This
pattern of change appears to involve a shift in the target of the
lipostatic system.
By extracting RNA from the hypothalami of short- and long-
day bank voles, we can compare the gene-expression profiles of
the major genes known to be involved in the lipostatic system.
 OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION
FIGURE 3 Body mass changes after transfer from short (8 h light:16
h dark) to long (16 h light:8 h dark) days in the bank vole Clethrionomys
glareolus (A). Gene-expression profiles in the hypothalamus for a panel
of neuropeptides known to be associated with energy regulation in
comparing short to long day–exposed animals (B) (redrawn from original
data in 173). LD, long day; SD, short day; AgRT, Agouti-related transcript;
MC3-A and -D, melanocortin-3 receptors in the arcuate and dorsomedial
nuclei, respectively; CRF, corticotrophin releasing factor.
The results of this comparison are illustrated in Figure 3B. This
comparison shows that some genes are differentially regulated,
in particular, the CART gene is upregulated in the long-day
group (173). This potentially indicates that CART has some
involvement in the lipostatic regulatory set point. Another
small-animal model system that is extensively characterized
with respect to responses to photoperiod is the Siberian hamster
Phodopus sungorus. On exposure to short photoperiods,
hamsters lose body weight and reestablish control at a much
lower level where ;30% of the body weight has been lost (Fig.
4A). Gene-expression profiles that compare long- and short-
photoperiod hamsters are also shown in Figure 4B (172). Some
parallel changes in the patterns for bank voles and hamsters are
apparent. In particular, the upregulation of CART is observed.
Interestingly CART was recognized in candidate-gene
screenings in humans as a potential candidate for influencing
obesity (163), although other studies of polymorphism linkages
between the CART gene and obesity suggest that the effects
are mostly on regional fat distribution (163a). These studies are
in their infancy, but the potential is clear. Once we know which
genes are involved in setting the lipostat target, we can start to
think about manipulating the system. These manipulations
could include production of agonists and antagonists to the
gene products and their receptors to turn someone with a high
target weight into someone with a low target weight.
How far in the future is this dream of manipulating body
weight by target resetting? Inevitably, progress depends on
making key breakthroughs in gene identification and control
2101S
Downloaded from jn.nutrition.org by on October 8, 2008
FIGURE 4 Body mass changes after transfer from long to short
days in the Siberian hamster Phodopus sungorus (A). Gene-expression
profiles in the hypothalamus for a panel of neuropeptides that are known
to be associated with energy regulation comparing short to long day–
exposed animals (B) (redrawn form original data in 172).
and the development of suitable pharmaceuticals. Because drug
evaluation and testing generally takes about a decade, this
could become a reality in 15–20 y. Drugs that mimic or interfere
with other components of the lipostatic system are already in
phases 2 and 3 of development and should be available to
health care practitioners within the next 5–10 y. Meanwhile,
the main alternative strategy is willpower. This does work, but
for a permanent solution, this needs permanent lifetime
commitment and struggle. The evidence suggests that few
people are able to sustain this. At present, the only alternative
solution that has almost guaranteed success is forced adherence
to energy restriction by surgical intervention. Surgical in-
tervention in 20% of the population is, however, beyond the
capacity of health care systems to deliver.
Drugs that manipulate the lipostatic system will provide
a valuable advance in the fight against obesity. Using these
drugs at the same time as calorie restriction means that patients
will no longer need to perpetually fight against the impetus of
their regulatory systems. Rather, we will use the system that
controls body weight to take it to a level that we want instead of
an arbitrary setting that is based on genetic inheritance. The
effect of treatment would be gradual, but unlike conventional
approaches that fight against one’s genes, an individual would
work with his or her genes, which will make the entire process
considerably easier. However, it should be clear that whatever
manipulation is envisaged, its success will only last as long as
the manipulation continues. If we administer drugs that lower
the lipostatic set point, they will only help suppress body fatness
2102S SUPPLEMENT
as long as the set point is altered. Once the drugs are
discontinued, the set point will (presumably) readjust to the
original level and the system will provide an impetus to regain
body weight. The same is true for all of the drugs that are based
on mimicking peripheral signals. Once the signal has gone, the
impetus to replace it by increasing fatness will return. Although
they are valuable, such drugs will need to be lifelong treatments
if they are to be effective. The ultimate ‘‘holy grail’’ solution is
to permanently switch the system so that the effects are also
permanent. Whether this is even possible without some form of
gene therapy (174,175) that may be politically unacceptable is
presently unknown.
Conclusion
Obesity is a serious condition that presently affects ;310
million people; an additional 800 million people are overweight.
Differences among individuals in their susceptibility to obesity
probably reflect, in large part, their genetic constitutions.
Attempts to fight against one’s genetic legacy are difficult to
sustain, so although most calorie-restricted diets are successful
in the short term, they are unsuccessful in the long term.
Presently research efforts are geared toward identifying and
ultimately manipulating the control system for body weight so
that solutions can work in harmony with (instead of against)
one’s genes. In the coming decade, we are likely to see further
dramatic advances in our understanding of this regulatory
system and novel drugs developed on the back of this improved
understanding.
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