Obesity Researchers Have Been Looking At The Wrong Gene

If you were investigating a crime scene, you wouldn’t just accuse the nearest bystander. The real culprit could be miles away.

In 2007, a team of British researchers announced that genetic variants within the FTO gene could predispose people to being fat. On average, people with one set of these variants weighed 1.6 kilograms more than people with none, and those with two sets—including one in six Europeans—weighed 3 kilograms more.

It was an important discovery. By studying twins, scientists had already shown that obesity runs in families, to an extent that can’t be explained by a shared environment. It was clear that some genes can influence how much we weigh (though, obviously, not exclusively*), but no one had identified any of them. FTO was the first. The media, as is their unfortunate wont, labelled it a “fat gene”.

Many later studies corroborated FTO’s connection to body weight. When scientists deleted the gene in mice, the rodents grew up thinner. When they switched the gene on, over and above its usual activity, mice ate more and put on weight. The pieces seemed to fit.

But right from the start, FTO was shrouded in mystery. No one really knew what the gene did, nor how it could influence our weight. And some parts of the FTO story just didn’t make sense.

When genes are switched on (scientists say “expressed”), the information in their DNA is converted into a related molecule called RNA. These RNA transcripts are then used to make proteins. But changes in FTO that were linked to obesity all cluster in a tiny part of the gene that doesn’t code for proteins at all—it gets cut out at the RNA stage.

Stranger still, these obesity-related changes didn’t seem to affect anything about FTO itself. They didn’t influence the way the gene is expressed, or the protein that it makes. And when scientists identified mutations in FTO that do impair its protein or change its expression, none of these were linked to obesity!

Now, Marcelo Nobrega from the University of Chicago thinks he has solved the mystery. His team have found that the obesity-linked bits of FTO reach across to a distant part of the genome to control another gene called IRX3. And it’s IRX3 that changes the levels of fat in the body.

Many scientists have fixated on FTO and tried to puzzle out what it does and how it affects body weight. These new results suggest that they have been looking at the wrong gene.

Nobrega’s team—primarily Scott Smemo, Juan Tena and Kyoung-Han Kim—used a technique that tests for physical contacts between different parts of the genome. Remember that the genome isn’t just a string of As, Gs, Cs, and Ts on a page—it’s a physical thing. It is made of DNA that twists and loops into three-dimensional spaghetti-like whorl, turning distant bits into close neighbours.

The team found that one such long-range connection between the obesity-related part of FTO and the region that switches on IRX3. The two regions were linked in mice, in zebrafish, and in human cells, which shows that the they have been interacting for at least 400 million years. And the team showed that the obesity-related FTO variants all change the activity of IRX3 in the human brain, and specifically in areas like the hypothalamus that control our metabolism and how much we eat.

What does IRX3 do? To find out, Nobrega’s team deleted the gene in mice. The results were stark. The animals grew up to be 25 to 30 percent lighter than typical rodents, and had much less body fat. They metabolism was higher because they tended to form calorie-burning brown fat rather than the energy-storing white fat. And they could seemingly eat with impunity; even on a high-fat diet, they didn’t put on weight.

So, it seems that a small part of FTO affects body weight by affecting IRX3 rather than FTO itself. Presumably, some variants in this region switch on IRX3 to an extreme degree and this hyperactive gene changes many aspects of our metabolism, making individuals more likely to pile on the pounds.

The details are still hazy, and the team is busy trying to clarify them. “We’ve made mice that make too much IRX3 in the brain,” says Nobrega, “and we’re hoping that they will become fat. Then we can see what’s different what’s different about them, whether it’s their appetite or other behavioural things.”

But wait a minute: what about those early studies showing that deleting FTO makes mice thinner? Nobrega thinks that these results were deceptive. “The mice didn’t just lose fat but also muscle and limb mass,” he says. Losing the gene didn’t produce a straight “anti-obesity” effect, but people were inclined to view it as such because of their biases.

What’s more, Nobrega’s team looked up the details of over 7,500 strains of mice that were missing specific genes, and found that almost a third of them had noticeable differences in size or weight! The FTO-less mice weren’t special. People interpreted their traits—their ‘phenotype—in the context of obesity because they were expecting an effect of that kind.

“I’ve been doing mouse genetics for many years,” says Nobrega. “There are some phenotypes that are very specific. There aren’t very many genes that will lead to retinitis pigmentosa if you knock them out. But bodyweight is very different. All types of things can make your bodyweight fluctuate. We should have been more careful about making interpretations about what this phenotype meant.”

Philippe Froguel from Imperial College London, one of the pioneers who first showed the link between FTO and obesity, is convinced by the new results. “From the beginning we were slightly suspicious,” he says. “I have been never impressed by the numerous papers published about FTO.”

Mark McCarthy from the University of Oxford, who also led one of the studies that brought FTO into the limelight, agrees. “It’s a timely reminder that when contemplating the scene of a crime, it is wise to look beyond those potential culprits standing nearest to the body, some of whom may well be innocent bystanders, and to look for ‘motive’ amongst those who may be standing a little distance away,” he says.

Nobrega thinks that these lessons probably apply to many other genes. The vast majority of genome-wide association studies, which look for genetic variations linked to traits and diseases, have identified variants in regions that don’t code for proteins—just like the obesity-related ones in FTO. And just as in FTO, scientists often assume that these variants affect the gene that they sit inside when they could actually be affecting one a long way away. “They’re investing in those genes and doing work on them without doing their due diligence.”

Reference: Smemo, Tena, Kim, Gamazon, Sakabe, Gomez-Marin, Aneas, Credidio, Sobreira, Wasserman, Lee, Puviindran, Tam, Shen, Son, Vakili, Sung, Naranjo, Acemel, Manzanares, Nagy, Cox, Hui, Gomez-Skarmeta & Nobrega. 2014. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature http://dx.doi.org/10.1038/nature13138

* A word of caution: despite what the media always implies when discussing the genetics of obesity, discovering an obesity-related gene does not mean that obesity is “in the genes” or that it’s something out of our control. Obesity is a complex condition with many underlying influences, including diet, activity, cultural norms, the environment we live in, media messages, our gut bacteria, and dozens more. Genes are part of this complex tapestry. They’re not deterministic—having an obesity-related variant doesn’t destine you to becoming fat. They don’t work in isolation from the environment but in tandem with it—they might affect our responses to food, or the way we process the calories we eat. It’s a case of nature via nurture. More on this here.