The factors that contribute to obesity extend beyond lifestyle choices alone. While genetics have a role to play, they do not provide a complete explanation for the inherited tendency to accumulate excess weight.

A recent study conducted by Charité – Universitätsmedizin Berlin and published in Science Translational Medicine sheds light on the involvement of a specific gene’s DNA code formatting, associated with satiety, in slightly increasing the risk of excess body weight, particularly in women.

This process, known as “epigenetic marking,” occurs during the early stages of embryonic development.

Being overweight, especially severe obesity, significantly raises the likelihood of developing various serious diseases such as cardiovascular conditions, diabetes, and cancer. It has become a pressing global health concern, as the number of overweight individuals continues to rise worldwide. According to the World Health Organization, within the European Region, nearly two out of three adults (59 percent) are overweight or obese.

But what exactly determines whether individuals will become overweight? While lifestyle choices are influential, genetic predisposition also plays a significant role. Studies have revealed that the body mass index (BMI) of identical twins exhibits a similarity ranging from 40 to 70 percent.

Even when raised in different environments, identical twins still demonstrate a notable degree of similarity in their BMI. Scientists have identified numerous genetic variations that impact an individual’s body weight and their susceptibility to obesity.

However, even when considering all these factors collectively, they fail to fully account for the observed heritability. Consequently, researchers have begun to suspect the presence of additional non-genetic elements that influence a person’s propensity to gain excess weight.

The satiety gene remains unchanged, yet it undergoes a reformatting process

The recent study conducted by Prof. Peter Kühnen and his team from the Department of Pediatric Endocrinology at Charité has revealed a significant finding regarding the POMC (pro-opiomelanocortin) gene, which is responsible for regulating the feeling of satiety. Although the satiety gene itself remains unchanged, the researchers discovered a notable “formatting” phenomenon associated with it.

According to their findings, women face an increased risk of being overweight by approximately 44 percent if there is an abundance of methyl groups attached to the POMC gene. Methyl groups are small chemical units utilized by the body to mark specific sections of the DNA code, effectively activating or deactivating genes without altering the underlying sequence. In essence, this process can be likened to highlighting a section of text without modifying the text itself. Termed “epigenetic marking,” this form of “DNA formatting” contributes to the observed effects.

During the study, the researchers analyzed the formatting of the POMC gene in a sample group of over 1,100 individuals. They discovered a greater presence of methyl groups on the satiety gene in obese women with a BMI over 35 compared to women with normal body weight. Prof. Kühnen notes that the 44 percent increase in the risk of obesity is comparable to the effects observed in individual gene variants. However, it is important to recognize that socioeconomic factors exert a stronger influence, potentially increasing the risk two to three times. The reason why the methylation effect exclusively manifests in women is still unknown and requires further investigation.

The researchers also observed that the formatting of the POMC gene occurs early during embryonic development. By examining the methylation patterns in identical and fraternal twin sets, they determined that the formatting of the satiety gene remained consistent in most identical twins, while there was minimal correlation in the fraternal twins. This suggests that the epigenetic marking of the POMC gene is established shortly after the fusion of egg and sperm cells, prior to the division of the fertilized egg into two separate embryos. These findings emphasize the critical role of the early stages of pregnancy in this process.

What factors contribute to the formatting process?

However, the extent of methylation that occurs in the satiety gene, and consequently the likelihood of an individual becoming overweight, can be influenced by various factors. Previous studies have suggested that the presence or absence of specific nutrients, which provide methyl groups, can impact epigenetic mechanisms. These essential nutrients include betaine, methionine, and folic acid, typically obtained through dietary intake. To gain further insights, researchers at Charité developed a novel technique using individual human stem cells to replicate and analyze how the methylation pattern is established during embryonic development, as well as how it is influenced by nutritional factors in a laboratory setting.

“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 explains. “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.”

Potential benefits of medications

In theory, individuals, particularly women, who face an increased risk of developing obesity due to methylation of the POMC gene, may find relief through the use of medications. Promising results have emerged from initial studies involving four severely obese women and one man with this specific type of “formatting” of the satiety gene. These participants were administered a specific drug that effectively suppresses hunger and is already approved for the treatment of obese patients with a POMC gene mutation. Within a span of three months after initiating the treatment, all five patients reported reduced hunger sensations and achieved an average weight loss of seven kilograms, which accounts for approximately five percent of their initial body weight. Encouragingly, some individuals opted to continue the treatment and experienced sustained weight loss.

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

Source: 10.1126/scitranslmed.adg1659

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