Scientists at the University of Cambridge in the U.K. say they 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.

Previous studies demonstrated that when the gene KSR2 (Kinase Suppressor of Ras 2) was deleted in mice, the animals became severely obese, according to the researchers. As a result, Sadaf Farooqi, Ph.D., 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.

“We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls,” wrote Dr. Farooqi and his team in an article (“KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation”) in Cell. “We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate, and severe insulin resistance.”

A slow metabolic rate can be found in people with an underactive thyroid gland, but in these patients thyroid blood tests were in the normal range. People have speculated for a long time that some individuals may burn calories more slowly than others. The findings in this study provide the first evidence that defects in a particular gene, KSR2, can affect a person’s metabolic rate and how their bodies processed calories.

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

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