Researchers link 'obesity gene' to hunger hormone

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LOS ANGELES — Researchers have further unraveled how a version of a gene linked to obesity risk causes people to gain weight — it makes them more likely to feel hungry after a meal and to prefer high-calorie foods.

Their study, published Monday in the Journal of Clinical Investigation, found that individuals who inherited the high-risk version of the FTO gene from both of their parents have higher levels of the appetite-stimulating hormone ghrelin in their bloodstream, which leaves them hungry even after eating. Real-time brain imaging also revealed that the FTO gene regulates the brain's responses to ghrelin and to images of food.

"This possibly explains why some people are more sensitive to overweight and obesity than others," said Dr. Jeremy Korman, a bariatric surgeon at Marina Weight Loss in Marina Del Rey, who was not part of the study.

A 2007 study found that people who have two copies of the "obesity-risk" version of FTO weighed about 6.5 pounds more, on average, than those who didn't have any copies of the variant. Other studies have shown that people who had the high-obesity-risk gene variant ate more those who didn't.

But exactly how FTO affected appetite and weight gain remained a mystery. Batterham's group hypothesized that gut hormones that regulate appetite-and the brain's responses-might be the missing link.

Their study marks the first examination of how FTO variation in humans regulates ghrelin and leads to obesity, said study coauthor Rachel Batterham, an endocrine and obesity researcher at University College London.

Batterham's group recruited 359 healthy, normal-weight European men. Among them, 45 had two copies of the obesity-risk version of FTO, while the rest carried the low-risk variant. The researchers matched the participants for body weight, fat distribution and social factors such as educational level, to make sure that any differences they saw were because of FTO and not to other physical or psychological characteristics.

A group of 10 men with the high-obesity-risk variant of FTO and 10 men with the normal version were asked to rate their hunger before and after a standard test meal. High-risk men felt hungrier than low-risk men after eating a meal, while blood tests revealed that they also had higher levels of ghrelin circulating through their bodies. Levels of ghrelin-secreted by stomach cells-normally peak right before a meal and subside immediately afterward.

The research team then used functional magnetic resonance imaging, or fMRI, in a different group of 24 subjects to measure their brain activity in response to images of high-calorie and low-calorie foods, as well as non-food items, before and after a meal. They asked the participants to rate the appeal of each image and measured their blood ghrelin levels.

Compared with their low-risk counterparts, subjects with the high-risk version of FTO found the images of high-calorie foods more appealing-even after a meal. The fMRI tests revealed that the brains of the two groups also responded differently to images of food before and after a meal and to circulating levels of ghrelin.

Researchers saw the most striking differences in the brain's reward regions, as well as the hypothalamus, which controls appetite. For example, low-risk participants preferred high-calorie foods before the meal, but preferred low calorie foods after eating. Researchers didn't observe this shift in obesity-risk individuals, who preferred high-calorie foods before and after eating.

The researchers also looked at mouse and human cells to tease out what was going on at the molecular level. Normally, FTO makes changes to ghrelin mRNA, which carries instructions for "building" the hormone. When FTO was produced at high amounts in these cells, ghrelin levels were higher. They also found that blood cells from people with two copies of the high-risk version of FTO had more ghrelin mRNA than people with the low-risk versions of FTO.

The study results could have important clinical implications, Dr. Korman said. For example, it could prompt pharmaceutical companies to develop drugs that help regulate ghrelin signaling.

But "the problem is that it's not as easy as it sounds," he said. Besides ghrelin, the gut releases other hormones that send "an opposite signal" that tell us that we're full and satisfied. "There are so many other signals interacting with the brain."

Batterham agreed. "This is one piece of a jigsaw," she said.