Novel genetic mutations cause low metabolic rate and obesity

Researchers believe the gene could be a useful therapeutic target for treating obesity and type 2 diabetes In the future, modulation of KSR2 may represent a useful therapeutic strategy for obesity and type 2 diabetes - Sadaf Farooqi Researchers from the University of Cambridge have discovered a novel genetic cause of severe obesity which, although relatively rare, demonstrates for the first time that genes can reduce basal metabolic rate - how the body burns calories. Previous studies (performed by David Powell and colleagues at Lexicon Pharmaceuticals in Texas) demonstrated that when the gene KSR2 (Kinase Suppressor of Ras 2) was deleted in mice, the animals became severely obese. As a result of this research, Professor Sadaf Farooqi from the University of Cambridge's Wellcome Trust-MRC Institute of Metabolic Science decided to explore whether KSR2 mutations might also lead to obesity in humans. In collaboration with Dr Ines Barroso's team at the Wellcome Trust Sanger Institute, the researchers sequenced the DNA from over 2,000 severely obese patients and identified multiple mutations in the KSR2 gene. The research was published online today, 24 October, in the journal Cell. 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. To investigate how KSR2 mutations might lead to obesity, Professor Farooqi's team performed a series of experiments which showed that many of the mutations disrupt these cellular signals and, importantly, reduce the ability of cells to use glucose and fatty acids.