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Slow metabolism gene could lead to childhood obesity

28 October 2013
Appeared in BioNews 728

A number of rare mutations in a gene that helps regulate how the body burns calories has been linked to an increased appetite and childhood obesity, according to a study from the University of Cambridge.

Together with researchers from the Wellcome Trust Sanger Institute, the team analysed the DNA of 2,101 patients with severe early-onset obesity. The study identified a number of mutations in the gene, KSR2, which is part of a group of genes responsible for how insulin is processed in the body and has previously been linked to obesity in mice.

Although mutations were seen in around one percent of the control group, they were more common in patients who became obese before the age of ten (around two percent). Patients who had a mutated copy of KSR2 showed increased appetite during childhood and a reduced metabolic rate compared to people with normal versions of the gene.

The combined effect is that patients with the mutation are more likely to consume more calories, but are also less efficient at burning them off, leading to weight gain.

Professor Sadaf Farooqi, who led the study, said: 'Changes in diet and levels of physical activity underlie the recent increase in obesity; however, some people gain weight more easily than others'.

Speaking to the Guardian, she added: 'This is the first time we can show that a gene contributes to a person's weight problem by slowing down their metabolic rate'.

Experiments also showed that when KSR2 is mutated, cells are unable to correctly use fatty acids and glucose for fuel. This defect could be corrected by the commonly prescribed diabetic drug metformin, the researchers observed.

So far, most other genes associated with obesity only affect appetite, not cellular metabolism (see BioNews 714). Therefore, the authors believe that drugs developed to change the activity of KSR2 could also provide new treatments for obesity and type 2 diabetes.

Professor Farooqi said: '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'.

However, the authors were keen to point out that KSR2 mutations are rare and most likely interact with other genetic and environmental factors to cause obesity.

As Dr Katarina Kos, from the University of Exeter Medical School, told the BBC: 'It is an exciting and interesting breakthrough, this is a new pathway predisposing people to obesity. But it does exist in obese and lean people so you still need the obesogenic environment'.

Blame Obesity On The Genes: Genetic Mutation Linked To Increased Hunger, Slower Metabolism
Medical Daily |  24 October 2013
KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation
Cell |  24 October 2013
Metabolism gene mutations can cause childhood obesity, find scientists
The Guardian |  24 October 2013
Novel genetic mutations cause low metabolic rate and obesity
University of Cambridge (press release) |  25 October 2013
Slow metabolism 'obesity excuse' true
BBC News |  24 October 2013
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