News article

Genetic mutation provides clues to battling childhood obesity

Posted:  Monday, October 28, 2013

As the number of children battling obesity continues to grow, researchers are racing to identify causes and possible interventions. Now, a new paper publishing October 24 in the journal Cell identifies a possible genetic root to the insatiable appetite and slow metabolism of some obese patients. The study, which sequenced 2,101 individuals with severe early-onset obesity, found that patients harboring mutations in a particular gene, KSR2, had an increased appetite and a slower metabolism than people with a normal copy of the gene. The findings suggest that drugs developed to modulate the activity of the protein encoded by the KSR2 gene could provide new treatment options for obesity and type-2 diabetes.

"Changes in diet and levels of physical activity underlie the recent increase in obesity; however, some people gain weight more easily than others" says study author Sadaf Farooqi of the University of Cambridge. "This variation between people is largely influenced by genetic factors. The discovery of a new obesity gene, KSR2, demonstrates that genes can contribute to obesity by reducing metabolic rate -- how well the body burns calories."

Farooqi and colleagues found that the gene KSR2 provides clues to how early-onset obesity can develop in some people. The deletion of KSR2 was previously shown to cause obesity in mice, underlining its role in controlling energy balance and metabolism. The genetic results in patients validated KSR2's involvement in the regulation of weight and metabolic processes in humans. Obese children carrying mutations in KSR2 displayed increased appetite, lower heart rate, slowed metabolism, and severe insulin resistance. Experiments in cells showed that the KSR2 mutations also impaired metabolic processes such as glucose and fatty acid oxidation.

"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" adds Farooqi.

The authors found that the diabetes drug metformin corrected the low levels of fatty acid oxidation seen in cells expressing the KSR2 mutations. These findings suggest that drugs like metformin may help obese patients harboring mutations in the KSR2 gene, offering exciting prospects for future pharmacological therapies and targets.

Laura R. Pearce, Neli Atanassova, Matthew C. Banton, Bill Bottomley, Agatha A. van der Klaauw, Jean-Pierre Revelli, Audrey Hendricks, Julia M. Keogh, Elana Henning, Deon Doree, Sabrina Jeter-Jones, Sumedha Garg, Elena G. Bochukova, Rebecca Bounds, Sofie Ashford, Emma Gayton, Peter C. Hindmarsh, Julian P.H. Shield, Elizabeth Crowne, David Barford, Nick J. Wareham, UK10K consortium, Stephen O’Rahilly, Michael P. Murphy, David R. Powell, Ines Barroso, I. Sadaf Farooqi, KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation, Cell, Available online 24 October 2013

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