Nav: Home

Scientists identify genetic factors that may cause some people to become obese

March 06, 2019

Obesity is a major public-health problem in the United States and around the world, with an estimated 650 million people suffering from the condition. One of the biggest challenges of this ever-worsening condition is figuring out why people become obese in the first place, and why some people are more vulnerable to obesity than others.

Now, scientists at The Rockefeller University and collaborators have identified a genetic mechanism that may play a role in at least 10 percent of all obesity cases. The findings, which could help identify individuals with treatable forms of the condition, shed new light on the biology of the hormone leptin, which is produced in fat cells and controls hunger. The amount of leptin in the bloodstream, and how the brain responds to it, help determine how much weight a person will gain.

The scientists report this week in Nature Medicine that, in mice, alterations in the cellular machinery that regulates leptin production can lead to a form of obesity treatable with leptin therapy. Evidence from human genetics studies further suggests that a similar mechanism may contribute to obesity in a subset of patients.

How leptin is finetuned

Discovered 25 years ago by Rockefeller scientist Jeffrey M. Friedman, the Marilyn M. Simpson Professor, leptin has been the subject of many thousands of studies exploring its structure and function. "We've learned a lot about leptin," says Olof Dallner, research associate and lead author of the new report, "but we didn't actually understand the basic biology of what regulates the leptin gene."

The gene coding for the leptin hormone is regulated by adjacent DNA sequences and regulatory factors that turn the gene on in fat cells, and that also controls the amount of leptin being made. As they explored this process, Dallner and his colleagues zeroed in on one of these regulatory factors, called a long non-coding RNA, or lncRNA, which they identified together with colleagues at the University of Pennsylvania.

When the researchers engineered mice without this specific lncRNA and fed them a high-fat diet, the mice became obese, but their fat cells produced significantly lower amounts of leptin. This unusual finding suggested to the scientists that the leptin gene could not express normal levels of the hormone without the lncRNA to help it along.  In comparison, a group of unaltered control mice fed the same diet gained weight and produced the expected amount of leptin.

Moreover, when these low-leptin mice were treated with injections of leptin, they lost weight--in other words, the hormone essentially cured them. And that, the researchers say, raises the exciting possibility that some humans whose obesity is caused by a similar genetic anomaly could also lose weight with leptin therapy. (A pharmaceutical form of leptin was approved by the U.S. Food and Drug Administration in 2014.)

The fact that there may be obese people with such potentially leptin-curbing mutations was suggested by analyzing data from a large study, known as a genome-wide association study (GWAS), that included the complete genetic profiles of more than 46,000 people. Together with collaborators at the Mount Sinai School of Medicine, the Rockefeller team found that people with alterations in the human version of the lncRNA had lower leptin levels.

A potentially-treatable subtype of obesity

The number of obese people whose disease may be the result of the dysregulation of the leptin gene is not known, Dallner says, but there is reason to believe it could contribute to as many as 10 percent of all obesity cases.

For Dallner, who spent the better part of nine years working on the project, the heterogeneity of the obese population--the fact that different people are obese for different reasons--is the most interesting takeaway from the research. "The important part for me is that we set out to study the leptin gene in mice, and we ended up concluding that different mechanisms can cause obesity in humans," he says.

Most obese people, he explains, become resistant to leptin (which would normally curb their appetites) because they have a lot of fat. Fat cells produce high amounts of leptin and, as the hormone accumulates, the brain appears to stop responding to it.

"But there is a large subset of humans who are obese and still are relatively low in leptin," Dallner says. "We now think that many of them may have these or similar gene variants that affect the expression of the leptin gene. This gives them less leptin from an early age, making them a little bit hungrier than everyone else."

These people remain sensitive to the hormone, however, and early clinical studies have shown that obese people with low leptin levels do in fact lose a significant amount of weight when treated with leptin. But the possible mechanisms underlying such cases were not understood, until now.

Dallner says that while the exact interplay between lncRNA and the leptin gene remains unclear, there is no doubt that the two are connected. "When we studied the lncRNA, we realized it was completely co-regulated with leptin. It's expressed where leptin is expressed. When leptin is down the lncRNA is down, and vice versa. That was really the key moment, when I saw that and thought, 'Something is really going on here.'"

 
-end-


Rockefeller University

Related Obesity Articles:

Obesity is in the eye of the beholder
Doctors have a specific definition of what it means to be overweight or obese, but in the social world, gender, race and generation matter a lot for whether people are judged as 'thin enough' or 'too fat.'
Type 2 diabetes and obesity -- what do we really know?
Social and economic factors have led to a dramatic rise in type 2 diabetes and obesity around the world.
Three in 4 don't know obesity causes cancer
Three out of four (75 percent) people in the UK are unaware of the link between obesity and cancer, according to a new Cancer Research UK report published today.
Obesity on the rise in Indonesia
Obesity is on the rise in Indonesia, one of the largest studies of the double burden of malnutrition in children has revealed.
Obesity rates are not declining in US youth
A clear and significant increase in obesity continued from 1999 through 2014, according to an analysis of data on United States children and adolescents age 2 to 19 years.
How does the environment affect obesity?
Researchers will be examining how agricultural and food processing practices may affect brown fat activity directly or indirectly.
Obesity Day to highlight growing obesity epidemic in Europe
The growing obesity epidemic, which is predicted to affect more than half of all European citizens by 2030, will be the focus of European Obesity Day to be held on May 21.
Understanding obesity from the inside out
Researchers developed a new laboratory method that allowed them to identify GABA as a key player in the complex brain processes that control appetite and metabolism.
Epigenetic switch for obesity
Obesity can sometimes be shut down.
Immunological Aspects of Obesity
This FASEB Conference focuses on the interactions between obesity and immune cells, focusing in particular on how inflammation in various organs influences obesity and obesity-related complications.

Related Obesity Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".