Metabolism gene mutations can cause childhood obesity, find scientists

Scientists have discovered that defects
in a single gene can cause a rare but
severe form of obesity by disrupting
the body's ability to burn calories.
The study is the first to show that
genetics can play a role in what
many had long suspected: that some
people put on weight more easily than
others because they burn calories
more slowly.
Researchers say the work will help
them to develop treatments for
obesity and also late onset, or type 2,
diabetes.
Scientists at Cambridge University
decided to investigate whether a gene
called KSR2 was important for
human obesity after researchers in
the US showed that blocking the gene
made mice profoundly overweight.
The UK team looked at the genomes of
more than 2000 severely obese people
and spotted scores of mutations in the
KSR2 gene. The gene is one of a group
that governs how hormones such as
insulin are used in the body and
ensures that cells grow, divide and
use energy properly. Lab tests found
that mutations in the gene caused
signals in cells to go awry and, in
many cases, damaged their ability to
process glucose and fatty acids, the
body's energy sources.
The study centred on people who
developed childhood obesity, a
condition that affects about 1% to 2%
of the severely obese, but a much
smaller proportion of the general
population. The scientists found that
people with KSR2 mutations had a
greater appetite in childhood but a
lower metabolic rate, so they
consumed more calories and burned
them slower than others. "This is the
first time we can show that a gene
contributes to a person's weight
problem by slowing down their
metabolic rate," said Sadaf Farooqi
who led the study. "Until now, the
genes we have found only affected
appetite. This affects appetite as well,
but it governs how you burn up
calories too." Details of the work are
published in the journal, Cell .
Further tests on the study participants
found that all of those with KSR2
mutations had severe insulin
resistance. Some of these patients lost
a substantial amount of weight when
given metformin, a diabetes drug that
lowers the blood sugar levels.
The discovery of a gene that is so
central to how the body uses energy
and puts on weight could lead to
therapies that help combat obesity
more generally. "This KSR2 molecule
is in all of us and it determines how
we burn calories. If we can find
ways to trigger or activate this
pathway, it might be more broadly
useful for patients with weight
problems or diabetes," Farooqi said.
While the rise in rates of obesity
worldwide is blamed largely on diet
and levels of physical activity, there
is huge variation in how much weight
people gain. Much of the variation is
because of genetics.