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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
Background ;600 million people face severe energy deficits and starvation
while at the same time, ;310 million people face a problem of
It is an ironic and rather sad fact that the two major chronic energy surplus and obesity (1). In some cases, these
nutritional problems that presently face the world are that problems exist alongside one another (2), but obesity is
1
Presented as part of the WALTHAM International Science Symposium: predominantly a problem of Westernized societies. In the last
Nature, Nurture, and the Case for Nutrition held in Bangkok, Thailand, October few years it has become an increasing problem throughout most
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.
of the world (e.g., 3–6). By 2000 the obesity problem had
Symposium proceedings were published as a supplement to The Journal of already grown to such an extent that the World Health
Nutrition. Guest editors for this supplement were D’Ann Finley, James G. Morris, Organization declared it was the greatest health threat facing
and Quinton R. Rogers, University of California, Davis. the West (7). Obese people carry around excessive amounts of
2
My work on obesity has been generously supported by the Scottish
Executive, the Biotechnology and Biological Sciences Research Council of the body fat, which in the absence of more direct measures, is
UK (Grant 1/S12830), and the Wellcome Trust. I am grateful to the organizers of generally estimated by combining measures of height and
the 2003 WALTHAM International Symposium for the invitation to present this work weight. The most common method of combining these
as a plenary address.
3
To whom correspondence should be addressed. E-mail: j.speakman@rri. measures is to divide body weight in kilograms (W) by the
sari.ac.uk. height in meters (h) multiplied by itself (i.e., W/h2). This is
2090S
OBESITY: GENETIC AND ENVIRONMENTAL INTERACTION 2091S
called the body mass index (BMI)4. On the BMI scale, people Because of the medical complications associated with
with an index .25 but ,30 are said to be overweight, and obesity, there is a statistically significant increased risk of
people with an index .30 are defined as obese. Although these mortality once BMI increases .25. Because the original data
definitions have been adopted by the WHO, there are several were derived for mostly white persons living in the U.S., there
well-recognized problems with this index. In particular, it does has been recent discussion over the relevance of this cut-off
not reflect body fatness changes very well when a person is also point for different ethnic groups (13). In particular, in Asians
changing his or her height over time. Consequently, BMI and Chinese, mortality has already started to increase at a BMI
cannot be used to reliably gauge the body fatness of children. In of 23–24. If a person has a BMI .30, then on average, his or her
addition, bodybuilders and some athletes, who have developed expected life span is reduced by 9 y compared to someone with
large amounts of muscle tissue, may also be misclassified as a BMI of 20–22 (14). There are ;30,000 premature deaths in
obese. Generally, however, in most adults, BMI correlates the UK annually that can be attributed to obesity (14). For
reasonably closely to body fatness (which is measured by more comparison, this is about the same number of individuals who
sophisticated scanning and imaging devices), particularly if die of lung cancer (;33,000 annually). Throughout Europe,
combined with measures such as the waist circumference (8). the deaths attributable to obesity exceed 300,000 annually,
Despite its limitations, the preferred use of BMI is justified which is ;1 in every 13 recorded deaths (15).
on historical grounds. During the 1930s, U.S. life insurance The health consequences of obesity combined with the fact
companies analyzed the factors that influence the probability that large numbers of people are afflicted by it has significant
that someone would redeem a life insurance policy (which economic consequences. In the UK, these costs were quantified
generally meant a person had died). Based on redemptions of in 2000 by the National Audit Office (13) to be ;£500 million
;5,000,000 policies issued in the 1930s, the factor the annually in direct health care costs and a further £2 billion
companies decided was the most effective predictor of mortality annually in wider costs to the economy. In the U.S., the total
was BMI. In fact, the life insurance companies discovered that economic costs of obesity in 1997–1998 were estimated at
mortality was lowest for individuals with BMIs between 20 and ;$92.6 to 99.2 billion annually when normalized to 2002
to eliminate all the disease consequences at once by treating rather than the effects of population genetics. The second facet
obesity itself. 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
Energy balance and obesity microstructure of the environment experienced by each
individual or may depend on genetic differences. An important
Obesity is a problem of imbalance between energy intake point to recognize is that genetics and environmental factors
and expenditure. Total energy demands can be partitioned into exert their effects on energy balance and obesity via effects on
several different compartments. The requirement to sustain our behavior and physiology (Fig. 1). There is no direct link
general cellular processes is known as the basal metabolic rate between our genes and our body weight or fatness. This is
(BMR). BMR is measured under strict conditions whereby the frequently misunderstood as is evidenced by discussions about
subject is completely inactive, is not digesting food, and is at whether obesity is caused by our genes or our behavior (e.g.,
a thermoneutral temperature. If we sit quietly, we burn more 28). As Figure 1 makes clear, these are not alternative causal
energy than BMR, and this is generally called the resting agents. Behavior and genes are different levels of the same
metabolic rate (RMR). After food ingestion, our metabolic rate causal framework. The question of ‘‘genes or behavior’’ makes
rises further; when we start to move around, it increases even no more sense than the question of ‘‘behavior or energy
more and is termed active energy expenditure. To balance our balance.’’ Consequently, although we might say that obesity has
total energy expenditure, we eat food. In the short term, a large genetic component to it, this doesn’t mean that the
expenditure and intake do not match closely, because we feed obese have somehow miraculously deposited enormous quan-
in discreet bouts, whereas expenditure is a continuous process. tities of body fat without eating too much food, or expending
Because of the laws of thermodynamics, which state that energy too little energy, or doing both.
can neither be created nor destroyed, the imbalance between
intake and expenditure requires that we also have the capacity
prevalence is even higher with ;50% obese. Socioeconomic parallel with the increased prevalence of obesity in both the
class and education also appear to be important factors, with U.S. (50) and Europe (48), and the decline is matched by a
the lowest educated groups having ;5% higher prevalence parallel increase in carbohydrate consumption (48,49).
than more educated subpopulations (31,32). Similar demo- It is clear that social changes involved activity reductions,
graphic patterns are reported for almost all Westernized and this was potentially combined with an increase in energy
societies. In addition, there are signs that this problem has consumption. We should be cautious, however, about drawing
achieved a truly global distribution during the last decade; simple cause-and-effect arguments from these correlations with
many Asian, South American, and African nations report that the spread of obesity. For example, enrollments at health clubs
obesity rates are increasing rapidly (3–6,33). have also expanded over the same period that obesity has
It is easy to identify some correlated societal trends to the increased. In addition, the stimulation of television and the
obesity epidemic. One of the factors believed to be important is availability of cheap electric lighting means that on average,
television viewing (34–39). By the early 1970s, televisions were individuals spend 2 h less each day asleep compared with the
already a virtually ubiquitous household feature in the U.S. and 1920s (51). Time spent sleeping is positively associated with
most of Europe. What has changed is the amount of obesity (42), so this change should be protective. Despite these
programming. We now have a choice of many different caveats, some intervention studies have assessed the roles of
channels to watch 24 h/d: there is always something to catch different factors. Studies in the U.S. were performed to try to
our attention and potentially keep us watching. By the late intervene in children’s television viewing habits to determine
1990s it was estimated that 20% of children in the U.S. were the impact on body fatness. These interventions show a
watching .6 h of television every day. Parental ratings of how significant effect on body weight. Surprisingly however, this was
much television a child watches are positively associated with not because the children adopted more active lifestyles when
the child’s BMI (35), and having a television in a child’s deprived of their viewing time. Rather, the major differences
bedroom is a significant risk factor for obesity (37); also, were in the consumption of snack foods: the children ate
television viewing is negatively associated with engagement in these when watching television, but not when engaged in
individually defined parameter under genetic control or energy balance (model 2) and feedback from the stored reserves
whether it is instead variable and itself dependent on body (model 3) might be difficult to resolve. This is because in most
composition such that when subjects have large fat reserves, circumstances, the two factors move in parallel. It is seldom the
they preferentially mobilize and deposit fat, but during periods case that someone could accumulate an energy deficit but not
of negative energy balance, they reduce the p ratio and start to affect levels of their stores and vice versa. To test between these
mobilize protein as well and thus autoregulate (to some extent) models, therefore, requires an experimental design that
their body composition (60). Several arguments suggest it is separates the different effects. If the system works as envisaged
unlikely that the p ratio is individually fixed (63). in model 2 (Fig. 2B), with a memory of energy deficit feeding
The p-ratio model can explain many features of energy back to drive intake and expenditure, then it seems likely that
balance without the need to invoke any regulatory signals this memory will decay over time. For example, if I starved you
generated by lean or fat tissues, particularly if the p ratio is for 24 h, you would feel hungry the next day. If I gave you free
fixed genetically (59). The model, however, is an inadequate access to food the day after you had starved, you would overeat
description of phenomena related to energy regulation (60– to compensate for the missing intake. However, if I stopped you
63). The main difficulty faced when using this model is from overeating for a week after your starvation day, but gave
explaining patterns of intake that occur after periods of food you enough to balance your energy demands, and then gave
deprivation. During food deprivation, subjects tend to reduce you free access to food, you would probably not feel as hungry as
their expenditure more than can be accounted for by the loss you did the day after you had starved. This is because
of metabolizing tissue (64–66). On refeeding, they also tend to the memory of the energy deficit had receded because of the
exhibit post-restriction hyperphagia. These patterns would not intervening time spent in energy balance. This decline in the
emerge if intake and expenditure were independent stochastic force of memories of energy deficit over time could be used to
variables linked only to storage by the p ratio. The salient issue separate regulation by model 2 from model 3 (Fig. 2C). The
is this: When we have been food deprived, where do the design is as follows: a set of subjects is placed on an energy-
feelings of hunger come from that cause us to subsequently restricted diet that provides fewer calories in food than they
be accounted for by the mass change, whereas under conditions because in parabiosis with a db/db mouse, a wild-type mouse
of energy surplus during the overfeeding part of the study, they receives a massive signal from the db/db animal; ‘‘thinking’’ it is
responded by elevating their energy expenditure. The con- massively over its target, the wild-type mouse shuts down its
tributions of changes in RMR and nonresting energy expendi- food intake to try to lose weight. Because the db/db partner
ture to these compensations were about equal. In other studies, keeps eating, however, there is always a signal telling the wild-
differential responses to overfeeding are reported: some type mouse not to eat, and eventually it dies of starvation.
individuals gained body weight whereas others did not. The Despite these insights, it was another 20 y before the signaling
extent of the weight gain was dependent on the extent to which compound was finally identified. The mutation causing the ob/
the subjects performed spontaneous activities to burn off the ob mouse signal was a single-base mutation in a gene located on
excess energy (79–81). chromosome 6 (84) (mapped to chromosome 7 in humans).
During the 1950s at about the same time that ideas were The consequence of this mutation was that instead of the gene
evolving about lipostatic, proteostatic, and glucostatic signaling the production of a full-length 167–amino acid
mechanisms of energy regulation, a spontaneous mutant mouse protein, the presence of a premature stop codon caused a much
occurred at The Jackson Laboratory in the U.S. This mouse, shorter, nonfunctional protein to be produced. The signal
which became excessively fat, was called the ob/ob mouse, protein was called leptin from the Greek root leptos, which
because it was clear that the original mutation was a single-gene means thin, because the animals that had full-length leptin
recessive defect that caused its (ob)esity. When heterozygous were lean.
ob/1 mice breed together, one quarter of the offspring are In the seminal paper on leptin (84), it was shown that leptin
homozygous ob/ob mutants, and they feed voraciously relative is produced exclusively in adipose tissue, which is as one might
to their littermates. They also have reduced metabolic rates and anticipate for a compound that acts as a lipostatic signal of the
lower body temperatures, and as they get older, they become size of body fat stores. Subsequent work shows other sites of
less active. In combination, this leads to a dramatic energy production at much lower levels in developing fetuses, placenta
imbalance, and the mice become very obese. On average, by 12 (85–88), and stomach (89). When recombinant leptin was
(a-MSH), whereas NPY/AgRP neurons secrete AgRP. a-MSH obesity may develop for two reasons. First, obese people may
is an agonist, and AgRP is an antagonist of both MC4-R and have broken lipostats; or second, the lipostats in obese people
MC3-R (109). When leptin molecules from the periphery dock may be set at very high target levels. After the discovery of
with their receptors on NPY/AgRP neurons in the ARC, there leptin, there was immediate interest in whether obesity was
is suppression of NPY release (110,111) and reduction in a result of deficient leptin production—a broken lipostat.
g-aminobutyric acid (GABA) release at the synapses where the Obese people might have abnormalities in their ability to
NPY/AgRP neurons meet the POMC/CART neurons. Under produce leptin in much the same way as the leptin-deficient ob/
the GABA-mediated disinhibition and combined with direct ob mouse. Imagine, for example, if my leptin production was
leptin stimulation, the POMC/CART neurons release a-MSH only half of the normal rate. My brain would think that I was
at the MC4-R on PVN neurons at the same time that the only half as fat as I actually am, and it would encourage me to
antagonist AgRP derived from the leptin-stimulated NPY/ eat more food and expend less energy until my fat content was
AgRP neurons is reduced. Secretion of a-MSH depends on high enough to redress the leptin-production deficiency. If this
successful cleavage of the POMC molecules, which is brought were the case, the potential to cure obesity would be in sight:
about by the proconvertase-1 enzyme. Additionally, the one could treat people with leptin (or drugs to mimic its action
stimulatory effect of a-MSH appears to depend critically on or stimulate natural leptin production) to trick the brain into
its acetylation status, which is also under regulatory control of thinking that one was fatter than was actually the case. The
acetylase-deacetylase enzymes. The increased a-MSH and regulatory system would then downregulate food intake and
reduced AgRP levels stimulate the MC4-R with two down- increase energy expenditure to redress the balance. The only
stream effects. First, the sympathetic system is stimulated and downside is that this would need to be a lifelong treatment,
releases noradrenaline at peripheral cells that express b-adren- because discontinuation would lead to decreased leptin levels
rgic receptors. In brown adipose tissue in rodents, this produces and resultant weight regain. However, the euphoria over the
an immediate stimulation of metabolic rate. At the same time, potential of leptin was short lived, because it was found (120–
food intake is inhibited. The resultant negative energy balance 124) that in general, fat people have very high leptin
Some key polymorphisms of MC4-R are associated with obesity, storage, and the risks of predation, which promote leanness
and in most populations that have been studied to date, (138–147). Because early humans likely also faced these
mutations of this gene account for ;3–5% of all morbid obesity contrasting selective pressures, they probably also evolved
(133). a regulatory system (i.e., a lipostatic system) that promotes fat
Overall then, completely broken lipostats explain only storage to avoid starvation but also prevents excessive fat
a small portion of the total numbers of obese and overweight storage to avoid predation (148). The set point of this system
people. What about the genetic ‘‘mis-setting’’ of lipostats at may have been temporally variable because of the differing
high targets, which then interact with the environment to selective pressures at different times of year. Several key events
generate the temporal and spatial patterns of susceptibility that in human evolution likely have dramatically reduced the risks
we presently observe? Is this a feasible alternative explanation of predation. These include the evolution of social behavior,
for the high prevalence of obesity? The negative-feedback which allows groups of humans to drive away predators and
model of body weight regulation has many similarities with alert each other of the presence of danger. Such behaviors are
thermostatic temperature regulation in a house (137). In that also observed in modern-day groups of apes and monkeys such
system, a room-temperature sensor compares the actual and as vervet monkeys, which have evolved complex signals to
desired room temperatures, and an effector system (the indicate the approach of different types of predators (149–152).
radiators) can be modulated to bring actual and desired states The harnessing of fire ;1.8 million y ago (153) and the
into balance. We can understand the interplay between genes construction of tools to actively aid defense would further
and the environment by using this thermostatically heated– enhance protection against the threat of predation. Under this
house analogy. Imagine houses have a whole range of release from constraint, it is feasible to imagine that target set
thermostatic temperature set points from cold to hot. If the points might drift upward at random because they would have
houses were all in the arctic and were poorly insulated, then all no selective consequences as long as actual body weights were
the house temperatures would be cold because even those with constrained by food supply. This would remove the strong
high set points (or broken thermostats) couldn’t get as hot as selection that imposed an upper limit on fat storage, but defense
weight loss. Whatever is claimed to be the mechanism, all permanent treatment for obesity is surgical intervention such as
successful weight-reduction diets work on the principle of gastric banding. This works because it forces people to comply
energy deficit. The major differences between diets are the with calorie restriction forever.
effects that they have on our short-term perceptions of hunger We can understand why calorie-restricted diets don’t work
and their side effects on other systems. Presently, popular diets for weight control by reconsidering the analogy of the thermostat
such as the Atkins diet rely on large quantities of dietary in a house (137). Imagine your thermostat is set very high and
protein almost to the exclusion of carbohydrate. The scientific your house is hot. You aren’t happy with this situation, but
basis for this diet is that there appears to be a hierarchy of because you don’t know how the thermostat works, you call in an
macronutrient effects on perceptions of hunger: fat is least ‘‘expert’’ who opens the sitting-room window. There is an
satisfying, carbohydrates next, and finally, the most satiating immediate improvement in the house temperature. Over the
macronutrient is protein (156). A diet that provides an energy next few days, the house cools to a more comfortable level, but it
deficit, where most of the calories come from protein, therefore is still a bit too warm; you need to open another window to keep
leaves one feeling less hungry than if the same deficit came from the temperature decreasing. Eventually you reach a desirable
a fiber-dominated diet. But weight loss is the same for the same temperature. Somebody comes by and says that you might have
energy deficit. The difference is that because perceptions of exposed yourself to some risks by opening your windows like
hunger are different, it may be easier to adhere to a high- that: your kids might get colds in the drafts, and you might get
protein diet than a high-fiber diet, and the longer one stays on burgled. You decide after a while that having the windows open
a diet, the more weight is lost. is not a great idea, and you close them. Immediately the
Potentially major problems exist with high-protein/low- temperature starts to rise again, and soon you are back to your
carbohydrate diets. First, these diets are generally deficient in boiling-hot house. Energy-restriction diets are like attempts to
micronutrients (which can be rectified by taking a vitamin fix your house temperature by opening a few windows. They are
supplement) and also, possibly, in carbohydrates that are effective, but they only work as long as you stay on them, and
important for optimal function of the central nervous system. they sometimes have undesirable side effects. Usually, dis-
animal models, therefore, is the best hope we have of finding serotonin interact (164), but as yet this is poorly understood.
general solutions to the obesity problem. If leptin production is Second, a phenomenon that is reported by marijuana users is
not the problem, then other possibilities are that the leptin fails that smoking the drug stimulates appetite. The discovery of
to cross the blood-brain barrier (162) or the signal is not read endogenous cannabinoid receptors (CB-1), which are putative
properly by the receptor system (both contributing to so-called drug targets, has led to the development of agonist and
leptin resistance). In the last couple of years, there has been antagonist drugs that bind to these receptors. There are already
enormous interest in other signals from the periphery that may CB-1 antagonist drugs that appear to generate significant
play a role in signaling energy status to the brain and may reductions in appetite and weight loss (165). The details of how
therefore be putative targets for drug development. The two they work, however, beyond interacting with the CB-1
major ones are ghrelin, which is a growth hormone secreta- receptor, is unclear. Finally, there is a whole class of drugs
gogue produced by the stomach, and PYY3-36, which is also that have weight gain as a side effect of their use. These include
a gut-derived signaling compound. The effects of these many of the antipsychotic treatments for schizophrenia such as
compounds remain controversial, and a vigorous debate is clozapine and olanzapine (166–168). Significant weight gain on
presently occurring over their effects on body-weight control. these drugs appears to include a combination of effects on
expenditure and intake (166). The drugs are known to be
The future active at many types of receptors in the brain including
histamine, dopamine, and 5-HT receptors (169). Their mode of
Although we have seen spectacular advances in our action relative to the established network downstream from
understanding of the molecular basis of body-weight regulation leptin is unclear.
during the decade since the discovery of leptin, and within the If we consider the model of the lipostatic system, it is evident
next decade we are likely to see drugs on the market that work that there are large blanks in our understanding of how this
with this system rather than against it to produce weight loss, system actually works. We know some of the signals that
there is still a great deal that we do not understand. Three emanate from the periphery to indicate energy status, but we
The results of this comparison are illustrated in Figure 3B. This and the development of suitable pharmaceuticals. Because drug
comparison shows that some genes are differentially regulated, evaluation and testing generally takes about a decade, this
in particular, the CART gene is upregulated in the long-day could become a reality in 15–20 y. Drugs that mimic or interfere
group (173). This potentially indicates that CART has some with other components of the lipostatic system are already in
involvement in the lipostatic regulatory set point. Another phases 2 and 3 of development and should be available to
small-animal model system that is extensively characterized health care practitioners within the next 5–10 y. Meanwhile,
with respect to responses to photoperiod is the Siberian hamster the main alternative strategy is willpower. This does work, but
Phodopus sungorus. On exposure to short photoperiods, for a permanent solution, this needs permanent lifetime
hamsters lose body weight and reestablish control at a much commitment and struggle. The evidence suggests that few
lower level where ;30% of the body weight has been lost (Fig. people are able to sustain this. At present, the only alternative
4A). Gene-expression profiles that compare long- and short- solution that has almost guaranteed success is forced adherence
photoperiod hamsters are also shown in Figure 4B (172). Some to energy restriction by surgical intervention. Surgical in-
parallel changes in the patterns for bank voles and hamsters are tervention in 20% of the population is, however, beyond the
apparent. In particular, the upregulation of CART is observed. capacity of health care systems to deliver.
Interestingly CART was recognized in candidate-gene Drugs that manipulate the lipostatic system will provide
screenings in humans as a potential candidate for influencing a valuable advance in the fight against obesity. Using these
obesity (163), although other studies of polymorphism linkages drugs at the same time as calorie restriction means that patients
between the CART gene and obesity suggest that the effects will no longer need to perpetually fight against the impetus of
are mostly on regional fat distribution (163a). These studies are their regulatory systems. Rather, we will use the system that
in their infancy, but the potential is clear. Once we know which controls body weight to take it to a level that we want instead of
genes are involved in setting the lipostat target, we can start to an arbitrary setting that is based on genetic inheritance. The
think about manipulating the system. These manipulations effect of treatment would be gradual, but unlike conventional
could include production of agonists and antagonists to the approaches that fight against one’s genes, an individual would
gene products and their receptors to turn someone with a high work with his or her genes, which will make the entire process
target weight into someone with a low target weight. considerably easier. However, it should be clear that whatever
How far in the future is this dream of manipulating body manipulation is envisaged, its success will only last as long as
weight by target resetting? Inevitably, progress depends on the manipulation continues. If we administer drugs that lower
making key breakthroughs in gene identification and control 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 18. Finkelstein, E. A., Fiebelkorn, I. C. & Wang, G. J. (2003) National
medical spending attributable to overweight and obesity: how much, and who’s
discontinued, the set point will (presumably) readjust to the paying? Health Aff. 22: 219–226.
original level and the system will provide an impetus to regain 19. Levy, E., Levy, P., Lepen, C. & Basdevant, A. (1995) The economic
body weight. The same is true for all of the drugs that are based cost of obesity—the French situation. Int. J. Obes. 19: 788–792.
on mimicking peripheral signals. Once the signal has gone, the 20. Schneider, R. (1996) Relevance and cost of obesity in Germany [in
German]. Ernährungs-Umschau 43: 369–373.
impetus to replace it by increasing fatness will return. Although 21. Swinburn, B., Ashton, T., Gillespie, J., Cox, B., Menon, A., Simmons, D. &
they are valuable, such drugs will need to be lifelong treatments Birkbeck, J. (1997) Health care costs of obesity in New Zealand. Int. J. Obes.
if they are to be effective. The ultimate ‘‘holy grail’’ solution is 21: 891–896.
22. Oppert, J. M. & Rolland-Cachera, M. F. (1998) Prevalence, time
to permanently switch the system so that the effects are also trends, and economic cost of obesity [in French]. Med. Sci. (Paris) 14: 939–943.
permanent. Whether this is even possible without some form of 23. Fernandez Real, J. M., Gutierrez, C., Ricart, W., Casamitjana, R.,
gene therapy (174,175) that may be politically unacceptable is Fernandez Castaner, M., Vendrell, J., Richart, C. & Soler, J. (1997) The TNF-
alpha gene Nco I polymorphism influences the relationship among insulin
presently unknown. resistance, percent body fat, and increased serum leptin levels. Diabetes 46:
1468–1472.
24. Gutierrez, C., Ricart, W., Casamitjana, R., Biarnes, J., Fernandez
Conclusion Castaner, M., Vendrell, J., Richart, C., Soler, J. & Fernandez Real, J. M.
(1997) A TNF-alpha gene polymorphism is related with insulin resistance, percent
Obesity is a serious condition that presently affects ;310 body fat and increased leptin. Diabetologia 40: 1198 (abs.).
million people; an additional 800 million people are overweight. 25. Savage, D. B., Sewter, C. P., Klenk, E. S., Segal, D. G., Vidal-Puig, A.,
Considine, R. V. & O’Rahilly, S. (2001) Resistin/Fizz3 expression in relation to
Differences among individuals in their susceptibility to obesity obesity and peroxisome proliferator-activated receptor-gamma action in humans.
probably reflect, in large part, their genetic constitutions. Diabetes 50: 2199–2202.
Attempts to fight against one’s genetic legacy are difficult to 26. Silha, J. V., Krsek, M., Skrha, J. V., Sucharda, P., Nyomba, B. L. G. &
sustain, so although most calorie-restricted diets are successful Murphy, L. J. (2003) Plasma resistin, adiponectin and leptin levels in lean and
obese subjects: correlations with insulin resistance. Eur. J. Endocrinol. 149: 331–
in the short term, they are unsuccessful in the long term. 335.
Presently research efforts are geared toward identifying and
47. Popkin, B. M., Haines, P. S. & Reidy, K. C. (1989) Food-consumption 80. Levine, J. A., Eberhardt, N. L. & Jensen, M. D. (1999) Role of
trends of U.S. women: patterns and determinants between 1977 and 1985. Am. J. nonexercise activity thermogenesis in resistance to fat gain in humans. Science
Clin. Nutr. 49: 1307–1319. 283: 212–214.
48. Alexy, U., Sichert-Hellert, W. & Kersting, M. (2002) Fifteen-year time 81. Levine, J. A. (2002) Non-exercise activity thermogenesis (NEAT). Best
trends in energy and macronutrient intake in German children and adolescents: Pract. Res. Clin. Endocrinol. Metab. 16: 679–702.
results of the DONALD Study. Br. J. Nutr. 87: 595–604. 82. Coleman, D. L. (1973) Effects of parabiosis of obese with diabetes and
49. Arnett, D. K., Xiong, B., McGovern, P. G., Blackburn, H. & Luepker, normal mice. Diabetologia 9: 294–298.
R. V. (2000) Secular trends in dietary macronutrient intake in Minneapolis–St. 83. Coleman, D. L. (1978) Obese and diabetes: two mutant genes causing
Paul, Minnesota, 1980–1992. Am. J. Epidemiol. 152: 868–873. diabetes-obesity syndromes in mice. Diabetologia 14: 141–148.
50. Willett, W. C. & Leibel, R. L. (2002) Dietary fat is not a major 84. Zhang, Y. Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. & Friedman,
determinant of body fat. Am. J. Med. 113: 47–59. J. M. (1994) Positional cloning of the mouse obese gene and its human
51. Dement, W. C. & Vaughan, C. (1999) The Promise of Sleep. Delacourt homologue. Nature 372: 425–432.
Press, New York, NY. 85. Hoggard, N., Hunter, L., Duncan, J. S., Williams, L. M., Trayhurn, P. &
52. Pérusse, L., Rice, T., Chagnon, Y. C., Tremblay, A., Rao, D. C. & Mercer, J. G. (1997) Leptin and leptin receptor mRNA and protein expression in
Bouchard, C. (2000) A genome-wide linkage analysis of genes related to the murine fetus and placenta. Proc. Natl. Acad. Sci. USA 94: 11073–11078.
energy and macronutrient intake in the Quebec Family Study. Obes. Res. 8: 26 86. Hassink, S. G., de Lancey, E., Sheslow, D. V., Smith-Kirwin, S. M.,
O’Connor, D. M., Considine, R. V., Opentanova, I., Dostal, K., Spear, M. L., Leef,
(abs.).
K., Ash, M., Spitzer, A. R. & Funanage, V. L. (1997) Placental leptin: an
53. Barsh, G. S., Farooqi, I. S. & O’Rahilly, S. (2000) Genetics of body-
important new growth factor in intrauterine and neonatal development? [Online]
weight regulation. Nature 404: 644–651.
Pediatrics 100: E1.
54. Kaplan, L. A. (2003) Body weight regulation and obesity. J. Gastro-
87. Masuzaki, H., Ogawa, Y., Sagawa, N., Hosoda, K., Matsumoto, T., Mise,
intest. Surg. 7: 443–451.
H., Nishimura, H., Yoshimasa, Y., Tanaka, I., Mori, T. & Nakao, K. (1997) Non-
55. Morin, C. L. & Eckel, R. H. (1997) Transgenic and knockout rodents:
adipose tissue production of leptin: leptin as a novel placenta-derived hormone in
novel insights into mechanisms of body weight regulation. J. Nutr. Biochem. 8: humans. Nat. Med. 3: 1029–1033.
702–706. 88. Senaris, R., Garcia Caballero, T., Casabiell, X., Gallego, R., Castro, R.,
56. Rosenbaum, M. & Leibel, R. L. (1998) The physiology of body weight Considine, R. V., Dieguez, C. & Casanueva, F. F. (1997) Synthesis of leptin in
regulation: relevance to the etiology of obesity in children. Pediatrics 101: 525– human placenta. Endocrinol. 138: 4501–4504.
539. 89. Bado, A., Levasseur, S., Attoub, S., Kermorgant, S., Laigneau, J. P.,
57. Rohner Jeanrenaud, F. & Jeanrenaud, B. (1997) Central nervous Bortoluzzi, M. N., Moizo, L., Lehy, T., Guerre-Millo, M., Marchand-Brustel, Y. &
system and body weight regulation. Ann. Endocrinol. (Paris) 58: 137–142. Lewin, M. J. M. (1998) The stomach is a source of leptin. Nature 394: 790–793.
106. Hahn, T. M., Breininger, J. F., Baskin, D. G. & Schwartz, M. W. 130. Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G. & Gruters,
(1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic A. (1998) Severe early-onset obesity, adrenal insufficiency and red hair
neurons. Nat. Neurosci. 1: 271–272. pigmentation caused by POMC mutations in humans. Nat. Genet. 19: 155–157.
107. Cheung, C. C., Clifton, D. K. & Steiner, R. A. (1997) Proopiomelano- 131. Graham, K. S. & Leibel, R. L. (2001) Yellow mice, red hair, and
cortin neurons are direct targets for leptin in the hypothalamus. Endocrinol. 138: childhood obesity: the melanocortinergic pathway in energy homeostasis. J.
4489–4492. Pediatr. 139: 177–181.
108. Schwartz, M. W., Seeley, R. J., Woods, S. C., Weigle, D. S., Campfield, 132. Kask, A., Rago, L., Wikberg, J. E. S. & Schioth, H. B. (1998) Evidence
L. A., Burn, P. & Baskin, D. G. (1997) Leptin increases hypothalamic for involvement of the melanocortin MC4 receptor in the effects of leptin on food
pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes intake and body weight. Eur. J. Pharmacol. 360: 15–19.
46: 2119–2123. 133. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. (1998) A
109. Zemel, M. B. & Shi, H. (2000) Pro-opiomelanocortin (POMC) de- frameshift mutation in human MC4R is associated with a dominant form of obesity.
ficiency and peripheral melanocortins in obesity. Nutr. Rev. 58: 177–180. Nat. Genet. 20: 113–114.
110. Yokosuka, M., Xu, B., Pu, S., Kalra, P. S. & Kalra, S. P. (1998) Neural 134. Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. C. &
substrates for leptin and neuropeptide Y (NPY) interaction: hypothalamic sites O’Rahilly, S. (1998) A frameshift mutation in MC4R associated with dominantly
associated with inhibition of NPY-induced food intake. Physiol. Behav. 64: 331– inherited human obesity. Nat. Genet. 20: 111–112.
338. 135. Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I., Ziegler, A.,
111. Schwartz, M. W., Erickson, J., Baskin, D. G. & Palmiter, R. (1997) Lep- Gerber, G., Sina, M., Gorg, T., Mayer, H., Siegfried, W., Fichter, M., Remschmidt,
tin regulation of hypothalamic neuropeptide Y (NPY) gene transcription in vivo H. & Hebebrand, J. (1999) Several mutations in the melanocortin-4 receptor
revealed by targeted mutation of the NPY gene. Diabetes 46: 229 (abs.). gene including a nonsense and a frameshift mutation associated with dominantly
112. Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E. & Haring, H. inherited obesity in humans. J. Clin. Endocrinol. Metab. 84: 1483–1486.
136. Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T. &
U. (1997) Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2
O’Rahilly, S. (2003) Clinical spectrum of obesity and mutations in the
(JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabe-
melanocortin 4 receptor gene. N. Engl. J. Med. 348: 1085–1095.
tologia 40: 1358–1362.
137. Speakman, J. R. (2003) Obesity: part 3—failed solutions and new
113. Schwartz, M. W., Figlewicz, D. P., Baskin, D. G., Woods, S. C. & Porte,
ideas. Biologist (Lond.) 50: 120–125.
D. (1992) Insulin in the brain: a hormonal regulator of energy balance. Endocr. 138. Adriaensen, F., Dhondt, A. A., Van Dongen, S., Lens, L. & Matthysen,
Rev. 13: 387–414. E. (1998) Stabilizing selection on blue tit fledgling mass in the presence of
114. Obici, S., Wang, J. L., Chowdury, R., Feng, Z. H., Siddhanta, U., Morgan, sparrowhawks. Proc. R. Soc. Lond. Ser. B Biol. Sci. 265: 1011–1016.
K. & Rossetti, L. (2002) Identification of a biochemical link between energy 139. Covas, R., Brown, C. R., Anderson, M. D. & Brown, M. B. (2002) Sta-
intake and energy expenditure. J. Clin. Invest. 109: 1599–1605. bilizing selection on body mass in the sociable weaver Philetairus socius. Proc. R.
160. Tschop, M., Strasburger, C. J., Hartmann, G., Biollaz, J. & Bartsch, 167. Reynolds, G. P. (2002) Weight gain, antipsychotic drug treatment and
P. (1998) Raised leptin concentrations at high altitude associated with loss of ap- pharmacogenomics. Pharmacogenomics 3: 567–570.
petite. Lancet 352: 1119–1120. 168. Werneke, U., Taylor, D., Sanders, T. A. & Wessely, S. (2003) Behav-
161. Heymsfield, S. B., Greenberg, A. S., Fujioka, K., Dixon, R. M., Kushner, ioural management of antipsychotic-induced weight gain: a review. Acta Psychiatr.
R., Hunt, T., Lubina, J. A., Patane, J., Self, B., Hunt, P. & McCamish, Scand. 108: 252–259.
M. (1999) Recombinant leptin for weight loss in obese and lean adults: 169. Cottier, Y. C., Berney, P. & Desmeules, J. (2003) Metabolic and
a randomized, controlled, dose-escalation trial. J. Am. Med. Assoc. 282: 1568– endocrine effects of atypical antipsychotics. Med. Hyg. (Geneve) 61: 755–761.
1575. 170. Lowell, B. B. & Spiegelman, B. M. (2000) Towards a molecular
162. Caro, J. F., Kolaczynski, J. W., Nyce, M. R., Ohannesian, J. P., understanding of adaptive thermogenesis. Nature 404: 652–660.
Opentanova, I., Goldman, W. H., Lynn, R. B., Zhang, P. L., Sinha, M. K. & 171. Mercer, J. G., Moar, K. M., Logie, T. J., Findlay, P. A., Adam, C. L. &
Considine, R. V. (1996) Decreased cerebrospinal-fluid/serum leptin ratio in Morgan, P. J. (2001) Seasonally inappropriate body weight induced by food
obesity: a possible mechanism for leptin resistance. Lancet 348: 159–161. restriction: effect on hypothalamic gene expression in male Siberian hamsters.
163. Chagnon, Y. C., Rankinen, T., Snyder, E. E., Weisnagel, S. J., Pérusse, Endocrinology 142: 4173–4181.
L. K. & Bouchard, C. (2003) The human obesity gene map: the 2002 update. 172. Mercer, J. G., Ellis, C., Moar, K. M., Logie, T. J., Morgan, P. J. & Adam,
Obes. Res. 11: 313–367. C. L. (2003) Early regulation of hypothalamic arcuate nucleus CART gene
163a. Challis, B. G., Yeo, G. S. H., Farooqi, I. S., Luan, J., Aminian, S., Halsall, expression by short photoperiod in the Siberian hamster. Regul. Pept. 111:
D. J., Keogh, J. M., Wareham, N. J. & O’Rahilly, S. (2000) The CART gene and 129–136.
human obesity: mutational analysis and population genetics. Diabetes 49: 872– 173. Peacock, W. L., Krol, E., Moar, K. M., McLaren, J. S., Mercer, J. G. &
875 Speakman, J. R. (2003) Photoperiodic effects on body mass, energy balance
164. Telles, M. M., Guimaraes, R. B. & Ribeiro, E. B. (2003) Effect of leptin and hypothalamic gene expression in the bank vole. J. Exp. Biol. 207: 165–177.
on the acute feeding-induced hypothalamic serotonergic stimulation in normal rats. 174. Muzzin, P., Eisensmith, R. C., Copeland, K. C. & Woo, S. L. C.
Regul. Pept. 115: 11–18. (1996) Correction of obesity and diabetes in genetically obese mice by leptin
165. Hildebrandt, A. L., Kelly-Sullivan, D. M. & Black, S. C. (2003) Antiobe- gene therapy. Proc. Natl. Acad. Sci. USA 93: 14804–14808.
sity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet- 175. Chen, G. X., Koyama, K., Yuan, X., Lee, Y., Zhou, Y. T., O’Doherty, R.,
induced obese mice. Eur. J. Pharmacol. 462: 125–132. Newgard, C. B. & Unger, R. H. (1996) Disappearance of body fat in normal rats
166. Nasrallah, H. (2003) A review of the effect of atypical antipsychotics on induced by adenovirus-mediated leptin gene therapy. Proc. Natl. Acad. Sci. USA
weight. Psychoneuroendocrinology 28: 83–96. 93: 14795–14799.