Mutations In A Metabolism Gene Could Predispose Some People To Severe Obesity

It's no secret that some people put on weight faster than others. But for the first time, scientists have identified a gene that is responsible for metabolism, or the rate at which a person's body burns calories. And for some people who have been obese since they were children, that particular gene is mutated and unable to carry out its normal functions.

Researchers at the University of Cambridge, led by Dr. Sadaf Farooqi, Ph.D., M.D., have determined that the KSR2 gene regulates metabolism, appetite and the way the body processes energy, such as glucose and fat. But mutations in the KSR2 gene mean that cells can't properly process glucose and fatty acids, which can lead to insulin resistance, obesity and a slower metabolism.

"It's been thought for some time that there's likely genetic differences in how people burn calories," said Farooqi in a phone interview with The Huffington Post. "There hasn't really been any proof until now that a gene or a set of genes can influence a person's metabolic rate."

Farooqi and her colleagues analyzed the KSR2 gene of two groups of people: 2,101 obese people who had been obese since they were younger than 10, and a control group of 1,536 people from a U.K. population-based study.

They found that 2.1 percent of people from the obese group had some kind of mutation on the KSR2 gene, more than double the amount found in the control group (1 percent).

"Basically 2 percent doesn't sound like very much," Farooqi explained, "but what it means is that having a variation of this gene is particularly rare and more often found in people who are severely obese than people who are normal weight."

However, the findings don't mean that only 2 percent of obese people are obese because of their genes. The other 98 percent of people might have a different gene that is also influencing their weight, Farooqi explained.

The people who had the gene mutation tended to be in the severely obese category, which means that they have a body mass index of 35 or higher (BMI is a ratio of weight to height). They also described having an abnormally large appetite when they were children (a condition that tapered off over time), and doctors determined they had low heart rates, severe insulin resistance and slow metabolisms.

Farooqi then sequenced the genes of family members related to the group with the gene mutation. She found that the family members who also had the same genetic mutation were also likely to be overweight or obese.

So what does this mean for parents of children who just seem to be a lot hungrier than their siblings and peers, or whose weight seems to be escalating at an alarming rate?

"For most people, the advice is still going to be that you've got to watch what you eat and you've got to do as much physical activity as you can, because we're doing a lot less of that in our society," said Farooqi. "At the moment, it's quite likely that our genes interact with the amount of exercise that we do and the food that we eat to influence our weight."

Farooqi is referring to a field of research called epigenetics, which is the study of how our environment and lifestyle choices affect our genes -- and even our children's genes. A person's genes aren't static, and instead can either be switched "on" or "off" depending on how a person lives his or her life.

For instance, the New York Times notes that a recent Swedish study showed that six months of exercise altered study participants' genes that are responsible for fat storage and developing obesity and diabetes.

For Farooqi, her study demonstrates that it's worth looking into whether children who become obese at a very young age have the KSR2 gene mutation. While there isn't currently a therapy that can address the mutation, simply knowing and acknowledging the genetic predisposition to obesity could, at least, lead to understanding among parents and children.

Studies like Farooqi's show that we're headed toward more personalized medicine in the future, notes Brian Parks, Ph.D. of the UCLA Lusis Lab in California.

"I imagine if you were found to carry specific mutations in KSR2, you would want drastic lifestyle modifications and maybe certain therapeutics would be beneficial," Parks wrote in an email to HuffPost. "This result is heading towards more personalized medicine in the future."

Parks, a researcher who studies the genetic causes of obesity and diabetes, released a study in January where 100 different strains of mice were fed the same high-fat, high-sugar diet. Weight gain among the mice varied greatly, and Parks and his colleagues determined that the differences were due to genetics. They also managed to identify several genetic regions associated with obesity in mice that overlap with humans.

"[KSR2] was not one of the genes that came out of our study in the mouse, but it certainly shows that the mouse is beneficial to finding new therapeutic targets to treat the ever-growing obesity and diabetes epidemic," Parks said in the email.

Farooqi delved deeper into the KSR2 gene after another study at Texas-based Lexicon Pharmaceuticals showed that deleting the gene in mice caused them to become extremely obese. She plans to explore in future studies exactly how the KSR2 gene works, which hopefully will lead to therapies for obese children with the mutated gene.

The obese people who were part of the study are members of a larger, U.K.-based research group called the Genetics of Obesity Study. Led by Farooqi, the research team conducts multiple experiments to learn more about the genetic factors that lead to severe and early weight gain. To learn more about the project, check out

Farooqi's study, "KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation," was published Oct. 24 in the journal Cell.

CORRECTION: A previous version of this story misspelled Brian Parks' last name. We apologize for the error.

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