Could a gene help make you obese?

By Dennis Thompson

Researchers have discovered a potential genetic explanation for why some people overeat and run a greater risk for obesity.

People who carry two copies of a variant form of the “FTO” gene are more likely to feel hungry soon after eating a meal, because they carry higher levels of the hunger-producing hormone ghrelin in their bloodstream, an international team of scientists found.

What’s more, brain scans revealed this double FTO gene variant changes the way in which the brain reacts to food and ghrelin. People with the double variant displayed different neural responses in the brain region known to regulate appetite and the pleasure/reward center that normally responds to alcohol and recreational drug use.

About one in every six people carries two copies of this FTO gene variant. These individuals are 70 percent more likely to become obese than people who carry other versions of FTO gene, according to background information in the study published July 15 in the Journal of Clinical Investigation.

“We’ve known for a while that variations in the FTO gene are strongly linked with obesity, but until now we didn’t know why,” said lead author Dr. Rachel Batterham. “What this study shows us is that individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more.”

Evolution may be responsible for the existence of this double variant in so many people.

“For the majority of the time that humans have existed food has been scarce. Having this genetic variant would have conferred a survival advantage,” said Batterham, head of obesity and bariatric services and director of Center for Obesity Research at University College London Hospitals.

The researchers first asked a group of 20 men —10 with the double variant, and 10 with a version of the FTO gene linked to lower obesity risk — to rate their hunger before and after a meal. Blood samples were taken to test their levels of ghrelin, a hormone secreted by the stomach that stimulates appetite.

Ghrelin levels normally increase before meals and fall afterward, but researchers found the men with the double FTO variant had much higher ghrelin levels after a meal and felt hungrier after eating than men who had the variation that carries lower obesity risk.

In the next step, the research team used functional MRI to measure how the brain responds to food images and ghrelin levels before and after a meal, using a different group of 24 men.

MRI scans revealed altered brain activity in the double-variant men, both in the appetite-controlling hypothalamus and the brain’s “reward” regions, which are known to respond to alcohol and recreational drugs. The altered activity occurred in response to food images and to the ghrelin in their bloodstream.

Further, men with the double FTO variant rated images of high-calorie foods more appealing after a meal that people with the low-risk variant.

“Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food — it’s a double hit,” Batterham said.

The doctors then took their research one final step further, using mouse and human cells to figure out what causes increased levels of ghrelin in men with the double FTO variant.

They found that increased expression of FTO gene “unlocks” the genetic template used to create ghrelin, leading to increased production of the hunger hormone.

The study provides “an important contribution to understanding the mechanistic process of how the FTO gene affects hunger and obesity,” said Emmanuel Pothos, an associate professor in the department of molecular physiology and pharmacology at Tufts University School of Medicine, in Boston. He was not involved with the study.

However, he noted that the FTO gene alone cannot explain the obesity epidemic. Other studies have found that people with the high-obesity-risk FTO variant weigh on average only 6.5 extra pounds more than people without the variant.

“There certainly are other factors here that are important that we don’t know about,” Pothos said. “The FTO gene has an important role here, but it’s not the only factor.”

The possibility exists that other hormonal and neural pathways related to obesity are unlocked through the same mechanism that causes increased ghrelin production, said Ruth Loos, director of the genetics of obesity and related metabolic traits program at the Icahn School of Medicine at Mount Sinai, in New York City.

“It’s a very complex interaction they describe. It’s a very nice story. It all fits nicely together, and it provides the first insights into how FTO might contribute to obesity,” Loos said. “But more research is required.”

Study author Batterham said this in no way should convince people with this genetic variant that they are helpless against obesity.

“At a therapeutic level, this arms us with some important new insights to help in the fight against the obesity pandemic,” she said. “For example, we know that ghrelin can be reduced by exercise like running and cycling, or by eating a high-protein diet. There are also some drugs in the pipeline that suppress ghrelin, which might be particularly effective if they are targeted to patients with the obesity-risk variant of the FTO gene.”

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