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Causes of obesity
John P.H. Wilding
ABSTRACT
Obesity is an increasingly common problem that is recognised a disease by the WHO. It is a major risk factor for the
development of type 2 diabetes because it causes insulin resistance and is associated with physical inactivity. Obesity
develops when energy intake exceeds energy expenditure over a prolonged period of time, leading to an accumulation
of body fat. Body weight is regulated by the hypothalamus, and there have been many recent advances in understanding
of energy balance that might help understand why some individuals develop obesity, and lead to new treatments. Both
genetic and environmental factors contribute to the development of obesity. The recent identification of rare single
gene defects that cause severe early onset obesity, such as deficiency of the hormone leptin, demonstrate that genetic
factors can be powerful determinates of body mass. However, obesity has been increasing rapidly throughout the world
in the last two decades, so it seems unlikely that this change has a genetic basis. It seems more plausible that the
increasing weight of most populations is an appropriate biological response to an abnormal environment, characterised
by easy availability of cheap, energy dense food, coupled with a massive decline in physical activity levels in the
population. The challenge in preventing type 2 diabetes is to reverse these trends, and help those already obese to
adopt a lifestyle that encourages weight loss, including a healthy diet and greater physical activity. Copyright © 2001
John Wiley & Sons, Ltd.
Practical Diabetes Int 2001: 18(8); 288–291
KEY WORDS
obesity; obesity genes; hypothalamus; leptin; diet; exercise

Introduction
Type 2 diabetes is characterised by
insulin resistance and progressive fail-
ure of b-cell function. In most cases,
insulin resistance predates the develop-
ment of diabetes by many years, and
although not all people with insulin
resistance go on to develop the disease,
it is clearly a major risk factor.1
Although it is likely that genetic vari-
ations in insulin action account for
some of the differences between indi-
viduals in terms of insulin action, insu-
lin resistance in the population is
strongly influenced by body fat con-
tent, particularly if the excess body
fat is distributed in the abdominal
John P.H. Wilding, DM FRCP, Reader in
Medicine, Clinical Sciences Centre,
University Hospital Aintree, Longmoor Lane,
Liverpool L9 7AL, UK
*Correspondence to:
John P.H. Wilding, DM, FRCP, Reader in
Medicine, Clinical Sciences Centre,
University Hospital Aintree, Longmoor Lane,
Liverpool L9 7AL, UK.
Received: 8 August 2001
Accepted: 17 August 2001
region.2,3 Furthermore, the presence
of insulin resistance and obesity is
associated with a clustering of abnor-
malities including dyslipidaemia,
hypertension, endothelial dysfunction
and abnormal clotting, all of which
serve to increase the risk of co-morbid
disease in patients with diabetes
(Figure 1). Epidemiological studies
clearly demonstrate that obesity is the
principal underlying cause of the con-
tinuing rise in the prevalence of type
2 diabetes worldwide.4 For all of these
reasons, understanding the causes of
obesity is fundamental to explaining
the pathogenesis of type 2 diabetes and
its complications. Furthermore, there
is now overwhelming evidence that
tackling the problem of obesity is the
key to preventing type 2 diabetes, high-
lighted most recently by the Finnish
Diabetes Prevention Study,5 and also
by surgical studies in morbidly obese
patients.6 Effective weight manage-
ment is also an important part of
treating patients with the disease. This
article will review the causes of obesity,
firstly by reviewing how weight is con-
trolled, using examples of rare obesity
syndromes to demonstrate some of the
Figure 1. Role of obesity in insulin resistance
and other features of the metabolic syndrome
principles involved, and discussing the
reasons behind the current obesity
epidemic.
What is obesity?
The WHO has defined obesity as a
body mass index >30 kg/m2, as this
is the point where the risk of several
obesity-related diseases, including dia-
betes, start to rise exponentially. How-
ever, body mass index is not always the
best indicator of adiposity, especially
with respect to diabetes risk, as
fat distribution is also important.
Furthermore, especially in some popu-
lations, the risk of diabetes is significant
even when body mass index is only

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Causes of obesity

slightly increased into the overweight to maintain normal metabolism in extent, energy expenditure. Energy
category (BMI >25 kg/m2), especially all the cells in the body. There is expenditure can be regulated by alter-
when the excess fat is in the abdominal an additional energy requirement ation of heat production (thermo-
cavity.7 Hence a more practical defi- involved in the digestion and assimila- genesis) in adipose tissue, and this is
nition is that obesity represents an tion of food, and finally there is the dependent on the sympathetic nervous
accumulation of excess body fat that has energy used during voluntary physical system, which is controlled by the
a significant adverse effect on health. activity. hypothalamus. At least 40 different
Obesity will develop when energy neurotransmitters may have a role in
intake exceeds energy expenditure for a The role of the these processes – those that increase
significant period of time, so to under- hypothalamus food intake generally decrease energy
stand the causes of obesity it is neces- Energy intake and expenditure are expenditure (i.e. in the direction of
sary to know what factors are involved both regulated by the central nervous energy conservation), whereas those
in regulating energy balance. system, with the hypothalamus playing that decrease food intake usually
a central role, although clearly some increase energy expenditure.8 The fol-
Regulation of energy aspects are also subject to voluntary lowing examples of rare obesity syn-
balance control. It is important to remember dromes illustrate this point quite well.
At the most simple level, regulation of that in evolutionary terms most of
energy balance is simply a case of these systems have the function of Hypothalamic tumours/
balancing food intake against the conserving energy in the face of short- surgery
energy used by the body. The first is age, rather than limiting it at times Damage to the hypothalamus from
easy to measure (at least in controlled of excess. The hypothalamus receives tumours such as craniopharyngiomas
laboratory conditions), the second signals from the periphery, both in the or from surgery for such lesions fre-
more difficult. Energy expenditure has short term, indicating the end of a quently results in increased appetite
three principal components, each of meal, and also in the long term, signal- and weight gain. Most of the weight
which can be regulated to some extent. ling body energy stores. These signals gain is thought to be related to
The first is the basal metabolic rate are integrated and help determine increased food intake, but a reduction
(BMR), which is the energy required future food intake, and also, to some in sympathetic nervous system activity,
leading to decreased heat production
Figure 2. Appetite control: Eating is regulated by a range of factors, including circulating in some tissues, and the anabolic effects
nutrients and hormones from the gastrointestinal tract, the sight and smell of food, taste, of hyperinsulinaemia secondary to
and memory of previous experiences. This involves several brain centres, but the hypothalamus
is of particular importance, as most signals pass through this part of the brain. Apart from
increased vagal activity may also con-
regulating eating, the CNS also determines a range of homeostatic responses to nutritional tribute.
status, including regulation of digestion and assimilation of food and metabolic rate. These
are controlled via the autonomic nervous system and secretion of pituitary hormones. Leptin deficiency or leptin
receptor mutations
Leptin is an adipocyte-derived hor-
mone. Its principal target tissue is
the hypothalamus. Mice with leptin
deficiency, or with mutations in the
leptin receptor, develop severe obesity
that is secondary to both increased
food intake and reduced energy expen-
diture.9 Similar defects have been
found in a small number of humans
with severe, early onset obesity.10,11 It
appears that the main problem in such
people is increased appetite; the meta-
bolic rate is normal. These subjects
may also have problems with fertility
due to hypogonadotropic hypogonad-
ism. This indicates another function
of leptin – as body fat rises, leptin
secretion increases, and at a certain
level this may act to trigger luteinising
hormone (LH) secretion at puberty.
Conversely, when leptin falls below a

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certain level, as occurs in anorexia
nervosa, then LH secretion is
inhibited, and menstruation stops.
Leptin acts in the hypothalamus by
altering levels of a number of neuro-
transmitters; these include neuropep-
tide Y (a powerful stimulator of
appetite, which also inhibits LH
secretion). When leptin levels fall, NPY
rises, and vice versa.12 Other targets
of leptin include preproopiomelano-
cortin, which is processed in the
hypothalamus to produce a- and
b-melanocyte stimulating hormone
(MSH). These act on the melanocortin
4 (MC4) receptor to reduce food
intake.13 Leptin levels are high in most
obese individuals, suggesting that the
dose response curve to leptin is flat
above a certain level – leptin is a
hormone that is most important in
its absence, and is thus unlikely to
contribute to most human obesity.
This is supported by the disappointing
results seen in trials of recombinant
leptin to treat obesity in humans.14
Genetic predisposition to
obesity
There is good evidence that adiposity
has a strong genetic component. There
is significant ‘clustering’ of obesity in
families, and a number of twin studies
have demonstrated that there is a high
(>50–70%) concordance rate for
obesity in identical twins, even if they
are not brought up in a shared environ-
ment.15 At present it is not known
whether this is due to shared defects
in the regulation of energy intake, or
differences in metabolic rate. In general
obese patients have higher metabolic
rates than lean subjects because they
have a higher muscle mass, but one
elegant study has demonstrated that
the within pairs of twins variance in
the amount of weight gained during
overfeeding is small, whereas the differ-
ence between pairs is much greater,
suggesting that the tendency to gain
weight when overfed may be geneti-
cally determined.16 However there is
also recent evidence that subjects who
compensate well for overfeeding by
increasing their metabolic rate tend to
be less thrifty in response to depri-
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Causes of obesity
Figure 3. Relationship between circulating leptin, body fat content and feelings of hunger. In
obesity, leptin levels are high, signalling adequate fat stores. Leptin may have small effects
day to day in lean individuals. When body fat (and therefore leptin) are very low, severe
hunger results. Factors other than leptin must drive hunger in most obese subjects.
vation, and this has no relation with
adiposity, so the contribution of these
responses to weight gain in the popu-
lation remain uncertain.17
Monogenic defects leading
to obesity in humans
These are rare, but a few defects have
been identified, and the phenotypic
characteristics are known. The molecu-
lar bases of the classical obesity syn-
dromes, such as Prader-Willi syndrome
and Bardet-Beidl syndrome, have not
been fully defined; although it is
known that Prader-Willi syndrome
is associated with a defect in an
imprinted gene on chromosome 15,
the precise molecular mechanism lead-
ing to weight gain is not known.18
More recently, some distinct causes of
severe childhood obesity have been
identified, that are similar to known
mutations causing obesity in rodents.
The first is leptin deficiency, which
is characterised by early onset, severe
obesity, with hyperphagia as the pre-
dominant problem (in contrast to
ob/ob mice, there is no evidence of a
thermogenic defect in leptin deficient
humans).10 The same phenotype is
seen in subjects with mutations of the
leptin receptor, but these subjects are
of course unresponsive to treatment
with exogenous leptin.11 Subjects have
page 290
been described with defects in the
MC4 receptor, resulting in loss of the
inhibitory signal and leading to early
onset obesity,19 and with defective
POMC processing.20 Finally, one sub-
ject has been described in whom a
defect in pro-hormone processing (due
to loss of the PC1 enzyme) resulted in
severe obesity together with inability
to process either preproinsulin or
ACTH in the normal way. The most
likely explanation for obesity in this
subject is a failure to produce a-MSH,
again resulting in reduced signalling
through the MC4 receptor.
Polygenic traits
There has been a considerable effort
to identify genes that might be more
common in obese subjects, in the hope
that this might lead to a better under-
standing of the causes of obesity.
Although at least 250 potential gene
loci have been identified,21 the search
has so far been disappointing, although
a polymorphism in the b3-adreno-
ceptor seems to be associated with a
higher risk of diabetes in obese sub-
jects, and increased weight gain in
morbid obesity, but not with obesity
itself. Candidate genes for obesity have
tended to include obvious targets, such
as genes encoding proteins involved in
regulating energy intake (such as NPY
Copyright © 2001 John Wiley & Sons, Ltd.
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or leptin), or those involved in con-
trolling energy expenditure (such as
UCP1 or the b3-adrenoceptor). How-
ever, it is quite possible that polygenic
traits leading to obesity might include
genes that are involved in functions
as diverse as the tendency to fidget,
physical activity levels or the preference
for high fat foods.
Environmental factors
It is clear that whatever the contri-
bution of genes to the propensity to
gain weight, obesity will only become
manifest if the environment is con-
ducive to weight gain, and this has
clearly been a major factor in the recent
rapid increase in obesity rates seen in
the last few years. The environmental
factors that are likely to contribute are
changes to the quantity or composition
of food in the diet, and changes in the
amount of physical activity undertaken
by the population.
Diet
Studies of total energy intake in the
population suggest that this has (in the
UK) been declining since the 1980s,
which is paradoxical, given that this is
the period that has seen the most
rapid and sustained increase in the
prevalence of obesity. However this
does not include soft drinks, alcoholic
beverages or food purchased and eaten
outside the home. This type of food
tends to be high in fat, and therefore
tends to be energy dense.22
Experimental studies show that con-
sumption of such food leads to less
satiety than with less energy dense
foods, and encourages overconsump-
tion, suggesting that the peripheral and
hypothalamic regulatory systems are
less sensitive to a high fat diet.
Physical activity
Levels of physical activity have declined
dramatically in the last 30–50 years.
There is greater reliance on the car,
there are fewer manual occupations
and there is increasing use of labour
saving devices. Leisure time physical
activity has also declined, in parallel
with increased use of television and
computer games. The latter is a par-
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Causes of obesity
ticular concern amongst children,
where rates of obesity are rising in an
alarming way.23
Social factors
Obesity, although a feature of affluent,
Western society, tends to be most
severe in subjects from social classes 4
and 5. It is likely that this is because
the diet tends to be higher in fat in
these groups, and levels of physical
activity are lower, especially with the
decline in traditional manual occupa-
tions.22
Conclusions
Obesity is the greatest preventable
cause of diabetes, and is becoming
more common. Social change is
undoubtedly the underlying reason for
the rapid increase in obesity, but as
obesity does not occur in everyone it
is clear that the biological response to
environmental change will determine
who is likely to become obese. In
some extreme cases, with well defined
genetic defects, obesity will occur
under almost any circumstances
(except in true famine), but the
majority of people will develop obesity
as part of a normal, and probably
polygenic, response to the very abnor-
mal (in historical and evolutionary
terms) environment in which we now
live. Solving the problem will require
a multifactorial approach – under-
standing the biology of energy balance,
and the underlying genetics, may
eventually help many patients with the
development of more effective drugs,
targeted behavioural interventions may
help some, and surgery a few, but the
greatest challenge will be to change
our way of living so that weight gain
does not become inevitable in a large
proportion of the population.
References
1. DeFronzo RA, Bonadonna RC, Ferrannini E.
Pathogenesis of NIDDM. A balanced overview.
Diabetes Care 1992; 15: 318–368.
2. Ohlson LO, Larsson B, Svardsudd K, Welin L,
Eriksson H, Wilhelmsen L et al. The influence
of body fat distribution on the incidence of
diabetes mellitus. 13.5 years of follow-up of the
participants in the study of men born in 1913.
Diabetes 1985; 34: 1055–1058.
3. Chan JM, Stampfer MJ, Ribb EB, Willett WC,
Colditz GA. Obesity, fat distribution and weight
Copyright © 2001 John Wiley & Sons, Ltd.
page 291
gain as risk factors for clinical diabetes in man.
Diabetes Care 1994; 17: 961–969.
4. WHO Study Group. Prevention of Diabetes
Mellitus, Report 844. WHO: Geneva, 1997.
5. Tuomilheto J, Lindstrom J, Erickson JG, Valle
TT, Hamalainen H, Ilanne-Perikha P et al.
Prevention of type 2 diabetes mellitus by changes
in lifestyle amongst subjects with impaired glucose
tolerance. N Engl J Med 2001; 344: 1343–1350.
6. Sjostrom CD, Lissner L, Wedel H, Sjostrom L.
Reduction in incidence of diabetes, hypertension
and lipid disturbances after intentional weight
loss induced by bariatric surgery: The SOS
Intervention Study. Obesity Res 1999; 7: 477–
484.
7. Ruderman N, Chisholm D, Pi-Sunyer X,
Schneider S. The metabolically obese, normal-
weight individual revisited. Diabetes 1998; 47:
699–713.
8. Wilding JPH, Widdowson PS, Williams G.
Neurobiology. Br Med Bull 1997; 53: 286–306.
9. Zhang Y, Proenca R, Maffei M, Barone M,
Leopold L, Friedman JM. Positional cloning of
the mouse obese gene and its human homologue.
Nature 1994; 372: 425–432.
10. Montague CT, Farooqi IS, Whitehead JP, Soos
MA, Rau H, Wareham NJ et al. Congenital leptin
deficiency is associated with severe early- onset
obesity in humans. Nature 1997; 387: 903–908.
11. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux
V, Cassuto D et al. A mutation in the leptin
receptor gene causes obesity and pituitary dysfunc-
tion. Nature 1998; 392: 398–401.
12. Widdowson PS,.Wilding JPH. Hypothalamic
neuropeptide Y and its neuroendocrine regulation
by leptin. Front Horm Res 1999; 26: 71–85.
13. Williams G, Harrold JA, Cutler DJ. The hypo-
thalamus and the regulation of energy homeo-
stasis: lifting the lid on a black box. Proc Nutr
Soc 2000; 59: 385–396.
14. Heymsfield SB, Greenberg AS, Fujioka K, Dixon
RM, Kushner R, Hunt T et al. Recombinant
leptin for weight loss in obese and lean adults –
a randomized, controlled, dose-escalation trial.
JAMA 1999; 282: 1568–1575.
15. Stunkard AJ, Harris JR, Pedersen NL, McCleam
GE. The body mass index of twins who have
been reared apart. NEJM 1990; 322: 1483-7.
16. Bouchard C, Tremblay A, Despres JP, Nadeau A,
Lupien PJ, Theriault G et al. The response to
long-term overfeeding in identical-twins. N Engl
J Med 1990; 322: 1477–1482.
17. Weyer C, Vozarova B, Ravussin E, Tataranni
PA. Changes in energy metabolism in response
to 48 h of overfeeding and fasting in Caucasians
and Pima Indians. Int J Obesity 2001; 25:
593–600.
18. Webb T, Clarke D, Hardy CA, Kilpatrick MW,
Corbett J, Dahlitz M. A clinical, cytogenetic, and
molecular study of 40 adults with the Prader-
Willi syndrome. J Med Genet 1995; 32: 181–185.
19. Yeo GSH, Farooqi IS, Aminian S, Halsall DJ,
Stanhope RC, O’Rahilly S. A frameshift mutation
in MC4R associated with dominantly inherited
human obesity. Nature Genet 1998; 20: 111–112.
20. Krude H, Biebermann H, Luck W, Horn R,
Brabant G, Gruters A. Severe early-onset obesity,
adrenal insufficiency and red hair pigmentation
caused by POMC mutations in humans. Nature
Genet 1998; 19: 155–157.
21. Perusse L, Chagnon YC, Weisnagel SJ, Rankinen
T, Snyder E, Sands J et al. The human obesity
gene map: the 2000 update. Obesity Res 2001;
9: 135–169.
22. Tackling Obesity in England. The Comptroller
General. HC 220. The Stationery Office:
London, 2001.
23. Prentice AM, Jebb SA. Obesity in Britain –
gluttony or sloth. BMJ 1995; 311: 437–439.
291
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