TOOLKIT

GENETICS OF
OBESITY

THE HERITABILITY OF OBESITY, LIKELIHOOD THAT

CHILDREN OF PARENTS WITH OBESITY WILL ALSO
BECOME OBESE, IS ESTIMATED TO BE BETWEEN
40% AND 70%

Obesity is a growing epidemic worldwide,
with 671 million adults and 124 million
young people suffering obesity today; this
represents a tripling of the prevalence
since 1975. By 2025, it’s expected that one-
fifth of adults will be suffering from obesity
worldwide.
There is a desperate need to find a solution
to the problem of obesity, as the compli-
cations of living with this condition for long
periods of time are severe. They include in-
creased risk of cancer, cardiovascular dis-
ease, metabolic conditions, dementia and
osteoarthritis.
The heritability of obesity (likelihood that
children of parents with obesity will also
become obese) is estimated to be between
40% and 70%.

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This figure however incorporates many
other social and economic variables, and so
is not a true reflection of the genetic causes
of obesity.
In order to determine which genes are re-
sponsible for the development of obesi-
ty, researchers need to determine which
genes individuals have, and see how these
relate to the likelihood of that individual
being obese. It is important when trying to
understand the causes of obesity to take
a multifactorial approach. Over the last
ENERGY INPUT > ENERGY EXPENDITURE
(CALORIES FROM FOOD)
The excess energy intake is stored as fat in
the body. However some people will store
MONOGENIC VS SYNDROMIC VS POLYGENIC
The types of genetic profiles which have
been linked to an increased likelihood of
obesity are categorised into three groups:
Monogenic obesity is the term used when
single gene mutations result in extreme
weight gain and early-onset obesity. Mono-
genic obesity is quite rare and accounts for
less than 1% of obesity cases.
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couple of generations, BMI has gone up
dramatically across the world, and has co-
incided with the growing reach of the ‘obe-
sogenic environment’, which is character-
ised by the widespread availability of cheap
calories and inactive lifestyles.
An unanswered question however, is why in
an equally obesogenic environment, some
individuals go on to develop obesity, while
others stay at a healthy BMI. The simple
equation that causes obesity is:
(CALORIES BURNT)
far more of it than others, even in very sim-
ilar environments.
They most commonly occur in genes of the
leptin/melanocortin axis involved in regu-
lating food intake, such as the gene for pro-
ducing leptin (LEP) or its receptor (LEPR).
Syndromic obesity is the term used when
obesity is one of a number of characteris-
tics associated with a genetic syndrome,
and usually includes mental disability and
developmental abnormalities. The most
common example is Prader-Willi syndrome,
which is caused by damage to the paternal
chromosome 15, and is characterised by
learning difficulties, short stature, insatia-
ble appetite and rapid weight gain.
In most cases of obesity, genetics plays a
much more subtle role. There are a large
number of genes which have been identi-
fied as having a small effect on weight regu-
lation by influencing our metabolism, phys-
iology, psychology and even our physical
activity level.
HOW GENES AFFECT BMI
APPETITE AND METABOLISM
Our genes code for all of the molecules
and cells which make up our body. From
enzymes used to cleave lipids, to neuro-
transmitters which can cause reactions in
the brain which induce a feeling of hunger.
If these particular genes are mutated,
whether to produce more or less of a par-
ticular molecule, or to not produce a mole-
cule at all, this can result in interruptions in
the energy intake/expenditure axis.
An important area in this axis is called the
hypothalamus, which is a region of the
brain that integrates messages from the
hormonal and nervous system, to deter-
mine energy expenditure, food intake and
nutrient partitioning.
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If an individual carries a large number of
gene variants which each promote weight
gain a small amount, overall they will have a
high risk of obesity. This is known as Poly-
genic obesity and is responsible for more
than 95 % of cases.
The extent of weight gain is dependent on
the interactions of these multiple genetic
factors with multiple environmental factors,
which result in diet and lifestyle behaviours.
Leptin is a hormone which is secreted by
adipose tissue, and is produced in propor-
tion to the level of fat in the body, indicat-
ing to the central nervous system long term
levels of energy storage. If leptin levels are
low, then the hypothalamus will trigger neu-
ral cells in the brain to stimulate appetite.
This message will be integrated in with sig-
nals of satiety and hunger from the gastro-
intestinal tract to regulate feeding.
It’s easy to see that if there are mutations
or variants in the genes coding for leptin,
its receptor, or any of the appetite-signal-
ling chemicals in the gut or brain, then this
complex system of energy balance can be
disturbed, leading to increased appetite
and overeating.
 HOW SIGNIFICANT ARE
THE GENETICS?

Although there is a large body of evidence that a collection of some of the most active
about the effect different genes have on genes only increased the odds ratio of be-
our BMI, it is important to remember that ing overweight by 3-14%.
apart from the monogenic and syndromic
The implication of this is that although it’s
conditions, genetics only plays a part in the
useful to understand the genetic underpin-
development of obesity, with environmen-
nings of weight regulation and appetite, so
tal, social, psychological and behavioural
far there are no easily identifiable genetic
factors all playing a role.
mutations which seem to explain the rapid
This is evident in the fact that obesity rates growth of obesity in the world right now.
have risen drastically within a couple of gen-
Instead it seems the environmental factors
erations - a time frame in which the genetic
and individual psychological factors play
make-up of populations would change neg-
the most significant role in determining
ligibly.
whether an individual develops obesity.
This is confirmed by a large study on the
effect of polygenic mutations, which found

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 NOTES

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