Metabolism gene mutations can cause childhood obesity

Scientists at Cambridge University decided to investigate whether a gene called KSR2 was important for human obesity after researchers in the US showed that blocking the gene made mice profoundly overweight. The UK team looked at the genomes of more than 2000 severely obese people and spotted scores of mutations in the KSR2 gene. The gene is one of a group that governs how hormones such as insulin are used in the body and ensures that cells grow, divide and use energy properly. Lab tests found that mutations in the gene caused signals in cells to go awry and, in many cases, damaged their ability to process glucose and fatty acids, the body’s energy sources.

The study centred on people who developed childhood obesity, a condition that affects about 1% to 2% of the severely obese, but a much smaller proportion of the general population. The scientists found that people with KSR2 mutations had a greater appetite in childhood but a lower metabolic rate, so they consumed more calories and burned them slower than others. “This is the first time we can show that a gene contributes to a person’s weight problem by slowing down their metabolic rate,” said Sadaf Farooqi who led the study. “Until now, the genes we have found only affected appetite. This affects appetite as well, but it governs how you burn up calories too.” Details of the work are published in the journal, Cell.

Further tests on the study participants found that all of those with KSR2 mutations had severe insulin resistance. Some of these patients lost a substantial amount of weight when given metformin, a diabetes drug that lowers the blood sugar levels.

The discovery of a gene that is so central to how the body uses energy and puts on weight could lead to therapies that help combat obesity more generally. “This KSR2 molecule is in all of us and it determines how we burn calories. If we can find ways to trigger or activate this pathway, it might be more broadly useful for patients with weight problems or diabetes,” Farooqi said.

While the rise in rates of obesity worldwide is blamed largely on diet and levels of physical activity, there is huge variation in how much weight people gain. Much of the variation is because of genetics.