'Thinness Gene' Could Explain Some People Stay Slim Without Trying

Scientists have identified a so-called "thinness gene" they believe could explain why some people stay lean without trying.

The gene, called Alk, is found in the hypothalamus, a part of the brain that controls appetite and how we burn fat.

To carry out the study, published in the journal Cell, the team searched a database of 47,102 people in Estonia aged 20 to 44 years old, which included clinical information and biological samples. They identified healthily thin people in the lowest 6th percentile of weight, those in the 30th to 50th percentile acted as the control group, and those in the 95th percentile were the obese group. The researchers pinpointed variants of genes that appeared to pop up more in the thin group. Next, they looked for the genes in flies to try to find those with a long evolutionary history, and landed on Alk as a likely "thinness gene."

To see whether Alk does help to control weight, the scientists turned off the gene in flies and found that levels of triglycerides, the form that most fats take in food and our bodies, went down. When they repeated this technique in mice, the animals got thinner and didn't become obese, despite having the same diet and moving the same amount as other mice.

The experiments in mice indicate that Alk affects a brain circuit that tells fat tissue to burn more calories, according to the team.

In general, healthily thin people "often have the desire to gain weight and have normal food intake and frequently snack, indicating they have a metabolic rather than hedonic low body weight," the authors wrote.

"Our genetic and mechanistic experiments identify Alk as a thinness gene, which is involved in the resistance to weight gain," they said.

An international team of scientists worked from Austria, Switzerland, Estonia, China, Australia, Canada, Sweden, and the U.S collaborated on the study. They worked together for eight years, co-author Dr. Josef Penninger, professor of the department of medical genetics at the University of British Columbia, told Newsweek.

Penninger explained: "There are thousands of studies published on Alk—in cancer. But the true physiological function of Alk was largely unknown," he said. "That Alk controls thinness in evolution was truly surprising. What we now show is that Alk is very specifically expressed in the brain and in the brain it controls a circuit that integrates genetics and feeding and environment to talk to the fat tissues and 'tell' that tissue to burn fat.

"Importantly, our mutant mice appear healthy and fine. Thus, one could indeed imagine to block Alk and try to control weight," but said that is far from being a reality.

Asked how the research could be used in the future and whether it could bring about treatments for obesity, Penninger said Alk is targeted by some cancer drugs, so we know it is "druggable."

But he said: "Obviously a pill cannot replace a healthy lifestyle, sports, eating healthy. But we gain weight as we age and of course if one could reduce that weight gain then the impact might be huge in the long term."

Sadaf Farooqi, a professor of metabolism and medicine at the U.K.'s University of Cambridge who did not work on the study, told Newsweek she was impressed by the team's approach, using genetic studies in humans, flies and mice.

However, the question of how Alk regulates weight and how important it might be for treating weight problems remains unanswered, she said.

The study was limited because the strength of the genetic association was modest, said Farooqi. "Geneticists would expect to see further testing in larger populations to be convinced, although that is difficult because it is hard to find a lot of people who are thin and well."

Farooqi said she was surprised that the gene works by increasing energy expenditure rather than suppressing appetite—which is what all the other genes known to affect weight in people predominantly do.

"More studies like this are needed because it's clear that some people can stay thin and that the reason for that is that a) they have less of the genes that we know increase a person's chance of being overweight and b) they have specific genes that keep them thin. Alk could be one of those genes," she said.

Dr. Philippe Froguel, professor of genomic medicine at the Imperial College London Faculty of Medicine, who did not work on the paper, was skeptical about the research and told Newsweek the findings in humans were "very weak." The study was limited because the authors didn't look for rare mutations that might cause leanness, he said.
Froguel said he and colleagues believe the findings in mice aren't explained by how the body breaks down fat, as the authors suggest. He said it is a common mistake to believe that the process of breaking down fats in the body influences energy balance.

"I think that the treatments against obesity that work reduce appetite and/or food absorption from the gut," he said, adding: "In my opinion leanness is due to education (of course in countries where you have enough to eat) or to brain-related changes in appetite."