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 / Updated  / Source: TODAY
By Maggie Fox

Obesity just got a lot more complicated.

Scientists have found 97 different DNA mutations that affect obesity — and they are all over your body. Many are in the brain, which surprised the experts. Some are linked to appetite but others will need more investigation.

And these mutations are very, very common.

A woman measures her torso fat.Shutterstock

A second study found 49 mutations that affect where that fat goes — and that helps explain why some people are apple-shaped while others are pear-shaped.

The bottom line: Obesity is a really complex disease and it is not a simple matter of calories in, calories out.

“People are expecting obesity to be caused by just one thing, but that’s not what’s happening.”

“What we set out to do is figure out what causes obesity. It is a huge health problem around the world,” said Dr. Elizabeth Speliotes of the University of Michigan, who led one of two studies published in the journal Nature on Wednesday.

The teams of hundreds of researchers from all over the world put together health studies of 340,000 people who’d been weighed, measured and given samples that could be DNA-sequenced. The researchers did what’s called a whole-genome study — a look at the entire genetic map — of everyone.

“We found 97 different changes in the genome that correlated very specifically with higher BMI,” Speliotes told NBC News. Body mass index or BMI is formula using height and weight and it’s a widely accepted measure of obesity.

“People are expecting obesity to be caused by just one thing, but that’s not what’s happening.”

Instead, people have changes in the DNA affecting the obvious factors, such as metabolism. But there are also mutations affecting blood vessel growth, some in the brain, and some that involve DNA that regulates other genes.

“Some play a role in energy expenditure, physical activity,” Speliotes said. “Many of them are just not known.”

And the mutations literally add up.

People can have as many as 194 of these genetic changes, because you get two copies of each gene — one from each parent. People who had 104 of the changes were on average 20-25 pounds heavier than someone who had just 78 of them, the researchers found.

Some of the genes are involved with regulation of cholesterol and blood sugar — and may explain why some people have high cholesterol or diabetes. “What I find exciting is we also found genetic variants that predispose to diabetes and heart disease,” she added.

“Also, variants that predispose to higher BMI that protect against diabetes and heart disease.” They may explain why some people can get fat yet escape diabetes, while others develop high cholesterol when they put on just a few pounds.

“Hopefully with this kind of information we can have more personalized or precision medicine in the futures,” Speliotes said.

Karen Mohlke, a professor of genetics at the University of North Carolina School of Medicine, led the team that found the genes involved in where people put on their fat.

"If we can figure out which genes influence where fat is deposited, it could help us understand the biology that leads to various health conditions, such as insulin resistance/diabetes, metabolic syndrome, and heart disease,” she said.

The findings also help explain why so many diet drugs fail to work in many people. “If your obesity is due to 'A' and you are given a drug that does 'Z,' it is not going to work for you,” Speliotes said.

The findings do hint at why one particular diet drug, called Qsymia, may work. It contains an anti-seizure drug called topiramate, and some of the changes seem to affect that drug’s mechanism of action.

With two-thirds of Americans obese or overweight, the issue’s a pressing one. “It really is the disease of our time,” Speliotes said. “We can’t stop it in part because we don’t know what causes it.”

“If you are unlucky enough to have these, you have to work harder than everybody else.”

Studies are starting to show that two different people can eat the precise same diet, exercise just the same amount, and one will gain weight while another will not. At least half of this must come down to genes, Speliotes said. And some people get dealt a bad genetic hand.

“If you are really, really motivated, if you starve yourself you can change that,” she said. “But these genes are working all the time. You can’t control them. They are in your body. They are working to get you to a certain point,” Speliotes said.

“If you are unlucky enough to have these, you have to work harder than everybody else.”

That said, the findings don’t get people entirely off the hook for bad habits.

“We are not saying there is a stronger genetic component than thought before,” Mohlke said. “Your DNA is shared by all the cells in your body. So diet and exercise and the environmental contribution are still important.”

Dr. Nicholas Timpson, a genetic epidemiologist at the University of Bristol in Britain who was not involved in the study, said the research doesn’t answer all the questions.

“This work does not hold a complete answer to variation in body composition, nor does it complete the genetic investigation of these traits. However, the traits being investigated are extremely relevant to population health,” Timpson said. And at least some of them could be altered with drugs or other therapies.