Factors Influencing Overweight Unveiled

What factors influence overweight? Aside from lifestyle, genes play a role, but they cannot entirely explain the hereditary proclivity to gain weight. According to a new study published in Science Translational Medicine by Charité—Universitätsmedizin Berlin, a type of structuring of the DNA code in one gene associated with satiety is connected with a slightly increased risk of excess body weight—at least in women. This “epigenetic marking” occurs early in the embryonic stage.

Overweight people, particularly those who are significantly overweight, are at a higher risk of a variety of serious diseases, including cardiovascular disease, diabetes, and cancer. It is a growing public health concern. Overweight persons are becoming more common all over the world. According to the World Health Organization, two out of every three persons (59 percent) in the European Region are overweight or obese.

But what factors influence whether they grow overweight? Along with lifestyle, genetic predisposition has a significant effect. Body mass index (BMI) similarity in identical twins ranges from 40% to 70%. Even identical twins raised in different families have considerable similarities. Scientists have discovered a number of genetic variations that influence a person’s body weight and, by extension, the chance of acquiring obesity.

Even when taken all together, they cannot explain the observed heritability. Researchers began to think that there must be other non-genetic variables influencing a person’s proclivity to gain extra weight.

The hunger gene is not altered, rather it is formatted

In a recent study, researchers led by Prof. Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité, uncovered one such risk. According to their findings, a high number of methyl groups adhering to the POMC (pro-opiomelanocortin) gene, which is responsible for the sense of fullness, raises women’s chance of being overweight by 44 percent.

Methyl groups are small chemical units that the body utilizes to activate or deactivate genes without changing the sequence of letters in the DNA. In other words, the impact is similar to highlighting a piece of a text without modifying it. This kind of “DNA formatting” is referred to as epigenetic marking.

The researchers examined the “formatting” of the POMC gene in over 1,100 participants for their study. They discovered more methyl groups connected to the satiety gene in obese women with a BMI greater than 35 than in normal-weight individuals.

A 44 percent increase in the risk of obesity is about the same as the effect that has been observed for individual gene variants as well,” says Kühnen. “By comparison, socioeconomic factors have a much stronger effect. They can increase the risk by a factor of two to three. As for why the methylation effect only shows up in women, we don’t know yet.”

Researchers discovered that the POMC gene is “formatted” extremely early in embryonic development by analyzing methylation patterns in more than 15 sets of identical and fraternal twins. While the “formatting” of the satiety gene was similar in the majority of identical twins, there was little association in fraternal twins.

“This indicates that the epigenetic marking of the POMC gene is established shortly after the egg and sperm cells merge, before the fertilized egg divides into two twin embryos,” explains Lara Lechner, the study’s first author, who works at the Department of Pediatric Endocrinology. This means the very early stage of pregnancy is crucial.

What factors influence formatting?
But what factors determine how much the satiety gene is methylated, and consequently the likelihood of being overweight? Previous research suggested that the presence or lack of specific foods that supply methyl groups could influence epigenetic processes. These nutrients include betaine, methionine, and folic acid, which are all normally absorbed by the food.

The Charité researchers were able to model in the lab how the methylation pattern is set during embryonic development and how foods alter it using a newly developed method utilizing individual human stem cells.

“On the one hand, our studies and others as well show that folic acid, betaine, and other nutrients have a limited effect on the extent of methylation,” Kühnen notes.

“We’ve observed that the ‘DNA formatting system’ is very stable on the whole, with cells compensating for minor fluctuations in the nutrient supply. On the other hand, there are indications that the variability of this ‘formatting’ develops at random. That means that it is not possible—not yet, at any rate—to externally influence whether a person has more or less methylation in the POMC region.”

Medications may be beneficial

Women who are at increased risk of acquiring obesity due to methylation of the POMC gene, at least in theory, could be given drugs to help them lose weight, according to preliminary research on four severely obese women and one man with this particular type of “formatting” of the satiety gene.

The volunteers were given a medication that suppresses hunger and has already been licensed to treat obese patients with a POMC gene mutation. All five patients reported less hunger three months after beginning medication. They lost seven kilograms on average, or around 5% of their overall weight. Some of them continued the procedure and lost weight.

“These findings show, for a start, that a POMC gene that has undergone epigenetic changes can in fact potentially be addressed through medication,” Kühnen says.

“Further large controlled studies will be needed to show whether treatment with this drug would also be effective over a longer period, and if so, how effective and how safe this type of treatment is. Overall, though, a medication like this would still need to be just one piece of a holistic treatment strategy.”

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