http://dx.doi.org/10.1016/j.cell.2013.09.058

Researchers from the Wellcome Trust Sanger Institute and the University of Cambridge have found a novel genetic cause of severe obesity. Although relatively rare, this is the first time that scientists have seen genetic variants that reduce the body’s ability to burn calories.

The team identified several rare variants on the gene KSR2. These mutations disrupt signaling of a biological pathway that, in turn, slows down metabolism. KSR2 gene could represent a new therapeutic target for the treatment of obesity and type 2 diabetes.

Changes in diet and levels of physical activity underlie the recent increase in obesity in the UK and worldwide, however there is a lot of variation in how much weight people gain. This variation between people is influenced by genetic factors and many of the genes involved act in the brain.

“For a long time, scientists and clinicians have speculated that some people may burn calories at a slower rate than others. Our findings provide the first evidence that defects in a particular gene, KSR2, may affect a person’s metabolic rate and how their bodies process calories.”

Dr Inês Barroso Co-lead author from the Wellcome Trust Sanger Institute

The team sequenced the DNA from more than 2,000 children with early-onset obesity and identified multiple mutations in the KSR2 gene. KSR2 belongs to a group of proteins called scaffolding proteins which play a critical role in ensuring that signals from hormones such as insulin are correctly processed by cells in the body to regulate how cells grow, divide and use energy.

They found that many of the mutations disrupt these cellular signals and reduce the ability of cells to use glucose and fatty acids. Patients who had the mutations in KSR2 had an increased drive to eat in childhood, but also a reduced metabolic rate, indicating that they have a reduced ability to use up all the energy that they consume.

“Up until now, the genes we have identified that control body weight have largely affected appetite. However, 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.”

Professor Farooqi Lead author from the University of Cambridge

The discovery of KSR2 variants contributing to obesity adds another level of understanding to the body’s mechanisms for regulating weight. The team is continuing to study the genetic factors influencing obesity, findings which they hope to translate into beneficial therapies in the future.