It is a slow metabolism after all: Scientists discover obesity gene

Mutations in "KSR2" gene prevent cells from processing glucose and fatty acids, scientists find

Science Editor

Obese people who claim they have a “slow metabolism” may have a point after scientists discover a gene that for the first time links being overweight with reduced metabolic activity.

Researchers from Cambridge University found that mutations in a gene known as KSR2 reduce the ability of cells to metabolise glucose and fatty acids, which provide energy.

These gene mutations are also more common in people with severe obesity than in the general, non-obese population, they found.

It has long been suggested that some people may be predisposed to obesity because of a “slow metabolism” but this is the first time that scientists have been able to identify a definite genetic basis for such an idea.

“It was something that most of us didn’t quite believe could happen because there wasn’t much evidence for it until now,” said Professor Sadaf  Farooqi of the University of Cambridge.

“Up until now, the genes we have identified that control body weight have largely affected appetite. This gene also increases appetite but it is also causes a slow metabolic rate,” Professor Farooqi said.

“KSR2 is different in that it also plays a role in regulating how energy is used in the body. In the future, modulation of KSR2 may represent a useful therapeutic strategy for obesity and type-2 diabetes,” she said.

Working with Ines Barroso of the Wellcome Trust Sanger Institute near Cambridge, Professor Farooqi sequenced the DNA from over 2,000 patients with severe, early onset obesity, and found that about 2 per cent of them had multiple mutations in the KSR2 gene – more than twice the rate found in non-obese people.

The study, published in the journal Cell, follows earlier work on mice that established the link between the gene and obesity. Mice that lacked the gene became severely overweight.

The KSR2 gene is responsible for some of the “scaffolding” proteins of the cell which play a crucial role in ensuring that signals from hormones such as insulin are correctly processed in the body to regulate how cells grow, divide and use energy.

The scientists found that patients with mutations in the KSR2 gene reported that they had an increased drive to eat when they were children but also a reduced metabolic rate, which meant they were unable to burn off all they energy they consumed.

Low metabolic rate is often linked with an underactive thyroid gland, but in these people their thyroid levels were within normal range, which meant that their metabolic deficit was caused by something else, such as defected KSR2 genes.

“This work adds to a growing body of evidence that genes play a major role in influencing a person’s weight and may be useful for developing new ways to treat people who are heavy and develop diabetes,” Professor Farooqi said.

A study published earlier this year by the same scientists found that children with the most severe kinds of obesity are more likely than other children to have one or more of four genetic variations in their DNA which could influence appetite and food metabolism.

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