They find a new factor that influences being overweight

He overweight and, above all, the obesity, can have serious health consequences because they contribute to the development of cardiovascular diseases, diabetes and cancer, among others, which is why excess weight has become a public health problem worldwide. Although an inadequate diet rich in fats and sugars, a sedentary lifestyle and genetic predisposition are considered the main causes of obesity, heredity cannot fully explain the propensity to gain weight.

Now, a new study carried out by scientists from the Charité – Universitätsmedizin Berlin and published in Science Translational Medicine has shown that a type of formatting of the DNA code in a gene related to the feeling of satiety is involved in a slightly elevated risk of excess body weight, at least in women. This “epigenetic marking” is established early during the embryonic stage.

While it is true that genetic predisposition plays a key role, along with lifestyle, the similarity of body mass index (BMI) in identical twins ranges from 40 to 70%. Even identical twins raised in different families still show the same significant similarity. Scientists have identified several genetic variants that influence a person’s body weight and their chances of developing obesity, but even taken together, they cannot explain the heritability that has been observed. Therefore, the researchers suspected that there must be additional non-genetic factors that influence a person’s propensity to gain weight.

What influences the “formatting” of the satiety gene

Researchers led by Prof. Peter Kühnen, Director of Charité’s Department of Pediatric Endocrinology, have just identified one of those factors that determine weight gain. Their findings reveal, in particular, that women’s risk of being overweight increases by around 44% if there is an especially large number of methyl groups attached to the POMC (pro-opiomelanocortin) gene, which is responsible for the feeling of satiety. Methyl groups are small chemical units that the body uses to mark the letters in the DNA code to turn genes on or off without changing the sequence of letters in the DNA. In other words, the effect is much like highlighting a section of text without retyping the text itself. This type of “DNA formatting” is known as epigenetic marking.

In theory at least, women who are at high risk of developing obesity due to POMC gene methylation could be given drugs to help them lose weight.

The researchers analyzed the “formatting” of the POMC gene in more than 1,100 people. They found more methyl groups attached to the satiety gene in obese women with a BMI of more than 35 than in women with normal body weight. “A 44% increase in the risk of obesity is almost the same as the effect that has been observed for individual genetic variants as well,” Kühnen notes. “By comparison, socioeconomic factors have a much stronger effect. They can increase the risk by a factor of two to three. As to why the methylation effect only appears in womenwe do not know yet”.

The POMC gene is “formatted” very early in embryonic development, as the researchers demonstrated by comparing methylation patterns in more than 15 sets of identical and fraternal twins. While the “formatting” of the satiety gene was the same in most identical twins, there was little correlation in fraternal twins. “This indicates that the epigenetic marking of the POMC gene is established shortly after the egg and sperm fuse, before the fertilized egg divides into twin embryos,” explains Lara Lechner, first author of the study, who works in the Department of Pediatric Endocrinology. This means that the very early stage of pregnancy is crucial.

But what influences the amount of methylation that the satiety gene undergoes and, therefore, the risk of a person being overweight? Previous studies showed that the presence or absence of certain nutrients provided by methyl groups could have an effect on epigenetic processes. These nutrients include betaine, methionine, and folic acid, which are generally absorbed through a person’s diet. A recently developed method involving individual human stem cells allowed these scientists to simulate in the laboratory how the methylation pattern is determined during embryonic development and how it is affected by nutrients.

“On the one hand, our studies and others also show that folic acid, betaine and other nutrients have a limited effect on the degree of methylation,” Kühnen notes. “We have observed that the ‘DNA formatting system’ is generally very stable, with cells compensating for minor fluctuations in nutrient supply. On the other hand, there are indications that the variability of this ‘formatting’ develops randomly. That means it’s not possible, at least not yet, to externally influence whether a person has more or less methylation in the POMC region.”

Drugs to treat obesity in individuals with POMC gene mutation

In theory at least, women who are at high risk of developing obesity due to POMC gene methylation could be given drugs to help them lose weight, as suggested by initial studies of four severely obese women and one man with this exact type of “formatting” of the satiety gene.

These individuals received a specific drug that curbs the feeling of hunger and that has already been approved to treat obese patients with a POMC gene mutation. Within three months of starting treatment, all five patients experienced less hunger and lost an average of seven kilograms, or about 5% of their body weight. Some of them continued treatment and continued to lose weight.

“These findings show, for a start, that a POMC gene that has undergone epigenetic changes can, in fact, be treated with drugs,” says Kühnen. “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 safe this type of treatment is. Overall though, a drug like this would still need to be just one piece of a holistic treatment strategy.”


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