The role of genes in obesity is one of science's great puzzles, even though researchers have learned much in recent years. They have identified dozens of genetic variants that increase the risk but are still untangling how these genes interact with other factors to help make us fat.

The experts are fairly confident about one thing, however: Except in rare instances, people genetically susceptible to obesity should not regard themselves as doomed.

"I like to say that obesity is 80 percent genetic and 100 percent environmental," says Philip F. Smith, co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, or NIDDK. "You won't become obese unless you overeat."

A growing body of research suggests that although genes can tilt you toward obesity, you can prevent it with healthy behaviors, including diet and exercise. You might have to work a little harder, but it can be done.

"For most people, I can say unequivocally that genes are not your destiny," Smith says. "They can predispose you to obesity, but only if you consume more calories than you burn off."

In the United States, more than a third of adults (36.5 percent) and 17 percent of youths are obese, according to the Centers for Disease Control and Prevention. Worldwide, obesity has more than doubled since 1980, with more than 600 million adults afflicted, according to the World Health Organization. The worldwide obesity rate among adults is 13 percent, far less than the U.S. rate.

Most of the world's people live in countries where being overweight or obese results in more deaths than being underweight, according to the WHO. Obesity is related to heart disease, stroke, Type 2 diabetes and certain types of cancer, including breast, colorectal and pancreatic. According to a CDC estimate, the medical cost of obesity in the United States was $147 billion in 2008, the most recent year for which figures are available.

The quest to learn more about obesity genes began nearly 30 years ago with the launch of the first "twins" studies that compared siblings who were reared together with pairs who were reared apart. "They found that obesity had a strong genetic component," says Marc Reitman, senior investigator and chief of NIDDK's diabetes, endocrinology and obesity branch.

But since then it has become apparent that "we live in an 'obesogenic' environment," Reitman says. "Obesity has been increasing since the 1970s, but genes are the same. Genes can't be the deciding factor, so it must be something in the environment. Both contribute."

Advances in molecular biology in addition to information from the Human Genome Project, including genome-wide association studies, have helped identify about 200 loci, or genetic markers, pointing to genes that increase the risk of obesity. A genome-wide association study scans thousands of individuals' complete sets of DNA looking for genetic changes that might be linked to a particular disease - in this case, obesity.

While not genes themselves, these markers - almost like signposts on a road - are DNA regions probably located near genes responsible for obesity risk. These association studies suggest that obesity involves "not one gene, but a combination of many genes, and their influence appears to be low," Reitman says. "It's amazingly complicated, but even the genetic variants that contribute the most have a low risk."

Researchers using a genome-wide association study identified the first obesity-linked gene variants in 2007, related to what is known as the "fat mass and obesity-associated" (FTO) gene on chromosome 16. People who carry an FTO variant have a 20 to 30 percent greater likelihood of becoming obese compared with those who don't carry a variant. The risk might be even higher for those who overeat and don't exercise, according to the Harvard T.H. Chan School of Public Health.

"Because the genetic variants for obesity are numerous, it is virtually impossible for someone to not carry any of these variants,''' says Frank Hu, chair of the school's department of nutrition, who has conducted a number of studies related to genes, obesity and diet. "However, some people may carry much fewer variants than others, but they can still become obese with an unhealthy diet and sedentary lifestyle."

"This is an important finding that has emerged in the last few years: that much depends on our own behaviors," he adds.

In a 2012 study, Hu and colleagues found that people genetically predisposed to obesity were more likely to experience increases in their BMI (body mass index, a measure of obesity) with a higher intake of beverages sweetened with sugar than their genetic peers who had fewer of these drinks.

Similarly, in a 2014 study, Hu and his team found that those with a genetic predisposition to obesity were more likely to gain weight if they ate fried foods four or five times a week than did those with the same genetic characteristics who shunned or rarely ate the high-fat items.

"We looked at the risk of becoming obese for those who were not obese at the beginning of the study," Hu explains. "Those with a genetic predisposition were more likely to become obese four years later, especially for those who consumed sugary beverages or ate fried foods on a regular basis. Although we did not specifically analyze weight gain per se, the results on obesity imply that the findings would apply to weight gain as well."

Regularly consuming fried foods or sugary drinks "exacerbates the genetic effects of obesity," Hu says. "Our findings indicate that genetic risk of obesity can be mitigated by simply changing an eating habit," he says.

Regular physical activity also seems to reduce the impact of genetics.

In 2011, researchers analyzed data from several dozen studies involving more than 200,000 people to examine the effects of exercise on those with an FTO gene variant.

Although those with the variant had a 23 percent higher risk of obesity than those who did not have it, the researchers found that being physically active lowered the risk. In fact, active adults with the gene variant showed a risk of obesity 27 percent lower than that of inactive adults.

"As a hypothetical example, for a group of sedentary people who carry one FTO gene variant, their likelihood of obesity is 10 percent," Hu says. "For a group of physically active people who also carry one gene variant, their likelihood of obesity would be lower, at 7.3 percent."

The results underscore "the importance of being physically active in obesity prevention, especially among those who are genetically predisposed to obesity," Hu says.

The current body of research shows that "it absolutely is not a life sentence to obesity if you have one or more of these variants," Smith says.

The only exceptions to what is called "common obesity" - where many genes are involved in raising the risk of obesity - occur in what is known as "monogenic" obesity. This is when a mutation in a single gene produces a very high risk of obesity, one that is difficult - sometimes impossible - to counteract. But these cases are extremely rare.

Still, researchers believe there is more to be done, including studies that look at whether any variants protect against obesity.

"We haven't thought enough about people who are resistant to the disease of obesity," Smith says. "There are people out there who should be obese - look at all the bad food they eat and their lifestyle - and they aren't."

Some such work is underway. Ayo P. Doumatey, a staff scientist at the National Human Genome Research Institute, for example, is studying the gene related to the production of adiponectin, a hormone secreted by adipose tissue, which is where the body stores fat. Obese people tend to have low levels of adiponectin, while thin people have more.

"Some people may have a variant of the gene that allows them to produce more," Doumatey says. "The more you have of it, the better. Individuals who tend to have more adiponectin do not develop obesity."

Scientists also want to know more about the interplay between genes and the environment. Obesity clusters in families, but family members also tend to cook and eat the same foods and also may engage in the same sedentary lifestyles.

Genes don't explain it all, but they could "determine tendencies or behaviors to eat certain kinds of foods or beverages," Hu says. "Genes may have weak effects overall, but they could have stronger effects in certain groups of people who are exposed to certain environments."

Experts also wonder whether genes affect willpower or compulsive eating behavior, such as the urge to snack after dinner.

"It could be when you and I go to a restaurant, you say 'no thanks' when the waiter offers us a rich dessert, but my genes predispose me to say 'yes,' " Reitman says.

"Why are some foods addictive? Why do we still eat when we feel full?" he adds. "The wiring and physiology around obesity is complicated, and we are just starting to try to figure it out."