Gloved hands hold up a used flow cell, which looks like a rainbow colored computer chip, dotted with a liquid DNA sample.

How much of a role does genetics play in obesity?

There are hundreds of genes that influence fat storage and metabolism. So, do we have any control over our weight at all? The experts weigh in.

A technician displays a used flow cell, which holds DNA for sequencing. To improve our understanding of the complex role genes play in the development of obesity scientists are comparing the genetic codes of people who have the disease with those who don't.
Photograph by Cristina Fletes-Boutte, St. Louis Post-Dispatch/Tribune News Service/Getty Images

Sometimes it’s bad genes, not just bad diet, that leads an individual to gain weight more easily than others.

Scientists have found that genetic mutations that make an individual feel less satisfied after a meal may be more common than previously thought, leading those who carry these gene variants to eat more frequently or to consume more calorie-rich foods.

"Obesity is not a choice,” says Giles Yeo, a geneticist who studies obesity at the University of Cambridge, United Kingdom. "The genetics of body weight is, by definition, the genetics of how our brain controls food."

Nearly a third of the adult population in the United States and almost one in six children and adolescents between the ages of two and 19 are currently overweight, according to the National Health and Nutrition Examination Survey. For the two in five American adults who are obese, this excess weight boosts the risk of developing many preventable diseases, including type 2 diabetes, high blood pressure, stroke, cardiovascular disease, and certain types of cancer. But what is causing this epidemic? Is it lifestyle or is our weight dictated by the genes we inherit?

While the kind of food-intake and the level of physical activity play a major role in growing population of obese people, science is revealing that, similar to height, between 50 and 80 percent of the variation between body weights can be due to subtle changes in some genes. While single genetic mutations that make obesity inevitable are super rare, the hundreds of genetic variations that each exert a tiny effect—making some of us slightly more vulnerable to gain weight—are more common. When someone inherits several of these variations their risk of obesity jumps significantly, particularly when combined with other lifestyle factors.

"We need the public to understand that we have so far, and very incorrectly, looked at obesity as a fault in a character,” says Naji Abumrad, an endocrine surgeon at Vanderbilt University Medical Center who treats morbidly obese patients and studies the effects of weight-loss surgery.

Obesity originates in the brain

That nature influences obesity was discovered serendipitously in 1949, when researchers at The Jackson Laboratory in Bar Harbor, Maine, noticed that a strain of their lab mice grew abnormally "plump" because they ate a lot of food and seemed to be perpetually hungry. It took 45 years to identify a mutation in a gene—named obesity—caused the mice to overeat and gain weight. A string of studies soon showed that the obesity gene produced a hormone called leptin, named for the Greek word leptós meaning “thin,” that attached to a receptor in the brain to signal satiety. Without sufficient leptin protein the mice felt hungry, ate, and got fat.

Subsequent studies revealed that leptin gene was just one member of a complex network of genes linked together in the so-called melanocortin pathway—which also includes insulin—to control appetite.

"Leptin is the hormone made in proportion to fat that tells the brain how much energy you have," says Roger Cone, an obesity researcher at the University of Michigan Life Sciences Institute.

Fat cells secrete leptin into the bloodstream, which cues the brain to feel full and helps burn fat. "Just like a thermostat on the wall that controls the amount of energy in a room, the leptin-melanocortin system controls the amount of energy you store as fat," says Cone. "There are other pathways as well that play critical roles in sensing leptin and converting that information into how much energy we burn and how much energy we acquire."

From a few mutations to many variants

Forms of obesity caused by mutations in just one gene, like the one that affected the mice at Jackson Labs, are estimated to be responsible for less than seven percent of morbid obesity worldwide. Only about six percent of severely obese children carry defects in known single genes that cause their condition.

Such single gene mutations, which become apparent early in life, are very rare, says Manfred James Müller, a nutritionist at the Christian-Albrecht University of Kiel in Germany. For example, only about a dozen cases of genetic leptin deficiency and only 88 cases of leptin receptor deficiency worldwide have been diagnosed.

More common are alternate DNA sequences, called polymorphisms, that lead to different versions of a gene that affect its function slightly.

To learn more about the roots of complex traits, like obesity, scientists use Genome-Wide Association Studies (GWAS) to identify variants of genes linked to a particular disease.

"We extract the DNA from thousands, or even a hundred thousand individuals," says Ruth Loos, director of the Genetics of Obesity and Related Metabolic Traits Program at Icahn School of Medicine at Mount Sinai. Loos and her colleagues then compare the complete set of DNA, or genome, of people who have obesity with those who don’t. The scientists then search for single 'letter' changes and estimate how likely those variants are associated with obesity.

Intrigued by why only some people develop obesity, Christian Dina, a genetic epidemiologist at Nantes University in France, compared the sequences of 2,900 obese patients with 5,100 people with healthy weight. Dina discovered that people with specific variations in a gene called FTO had a 22 percent higher risk of becoming obese. But figuring out why they raise the risk or how these gene variants function can take many more years of research.

For example, studies have shown that a different variant of the FTO gene that affects one in six adult European males can increase their risk of becoming obese by 70 percent. People with this obesity-risk FTO variant have higher levels of the hunger hormone, ghrelin, circulating in their blood, which makes them feel hungry soon after eating a meal. Brain-imaging studies of people carrying this gene variant also reveal that these individuals respond differently to ghrelin and to pictures of food.

For some, a silver lining?

But not all gene variants linked to obesity are bad. A rare gene variant has also been found that can protect against obesity. A study of more than 640,000 people from Mexico, the U.S., and the United Kingdom, found that people who carried an inactive copy of a gene active in the hypothalamus—which regulates hunger and metabolism weighed about 5.3 kilograms (nearly 12 pounds) less and were half as likely of being obese compared with those with working versions.

“But most of the studies that link risk of getting obese with the genetic variations so far have been done on the European and white population,” says Abumrad. That means that the findings may not be relevant to people with different ancestry. The ambitious “All of Us Research Program” launched by the National Institutes of Health in 2018—which plans to recruit at least one million people of various ethnicities—may help to accurately assess the extent of the genetic predisposition to obesity.

Diet and lifestyle are the main drivers in the obesity epidemic, says Dina. "But there is a strong genetic basis in the difference of reaction to the obesogenic environment.”

Dina's, Yeo's and other's work is revealing that variations in many genes involved in our feeding behavior can frequently be linked with a range of obesity traits, such as BMI, body fat percentage, levels of leptin in blood, etc. So far, scientists have identified more than 1,000 gene variants that each explain a very small part of the difference in body weight between people. Their association with increased risk to gain weight usually manifests later in life resulting from an interaction between the presumed risk genes and lifestyle variables, explains Müller.

However, the trends toward increasing obesity worldwide have more to do with lifestyle choices since there are no hints of drastic change in the occurrence of genetic variations across generations. In fact, studies have shown that consumption of fried food in conjunction with the underlying genetic background plays a big role in developing obesity.

While frequent consumption of high-calorie food may cause people with obesity-associated genes to gain weight faster, awareness, prevention, and exercise are very effective in avoiding the obesity.

“Having the same FTO allele that my father has doesn’t mean it will give me obesity,” says Dina. “I have a slightly increased chance, but I can avoid it.”

Editor's Note: This article originally misstated Christian Dina's affiliation. It is Nantes University, France.

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