Genetic variants decrease rate of metabolism

Defects to gene reveal potential new therapeutic targets against obesity and type 2 diabetes

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

Schematic representation of full length KSR2 (Q6VAB6), indicating the location of each of the mutations identified in individuals with severe early-onset obesity and those found in controls (shown in grey)

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.

More information

Funding

This work was supported by the Wellcome Trust, Medical Research Council, NIHR Cambridge Biomedical Research Centre, and European Research Council.

Participating Centres

• University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC
• Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
• Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK
• Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA
• Institute of Child Health, University College London, London WC1E 6BT, UK
• University of Bristol and Bristol Royal Hospital for Children, Bristol BS2 8BJ, UK
• Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
• MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
• MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK