2023-07-20 13:53:26
What determines being overweight? In addition to lifestyle, genetic predisposition plays a role, but genes cannot fully explain the inherited propensity to gain excess weight. According to a team of researchers from the Charité University of Medicine in Berlin there is a new element that can be key in women: the formatting of DNA or epigenetic marking that is established during the embryonic stage.
The good news is that weight loss drugs could be effective, as shown in a small pilot trial of 4 overweight people who received a specific drug that curbs feelings of hunger and has already been approved to treat obese patients with a POMC gene mutation.
Overweight people, especially those who are severely overweight, are at increased risk of a number of serious diseases, including cardiovascular disease, diabetes, and cancer. It is an increasingly serious health problem. Around the world the number of overweight people is increasing. In Europe, two in three adults (59%) are overweight or obese, according to the World Health Organization.
But what determines that people become overweight? Genetic predisposition plays an important role, along with lifestyle.
However, it has been seen that the body mass index (BMI) in identical twins it can be between 40% and 70%. Even identical twins raised in different families show the same significant similarity.
Scientists have identified several different genetics that influence a person’s body weight and, with it, the risk of developing obesity. But even taken together, they cannot explain the observed heritability. The researchers began to suspect that there must be non-genetic factors additional factors that influence a person’s propensity to gain excess weight.
The satiety gene is not altered, but formatted
Researchers led by Peter Kühnen, Director of the Department of Pediatric Endocrinology of the Charitéhave now identified one such factor in their study published in «Science Translational Medicine».
According to their conclusions, the risk of being overweight in women increases by around 44% if there is a particularly high number of methyl groups attached to the POMC (pro-opiomelanocortin) gene, responsible for the feeling of satiety.
The researchers explain that methyl groups are tiny chemical units that the body uses to mark the letters of the DNA code in order to activate or deactivate genes without changing the sequence of DNA letters. In other words, the effect is very similar to highlighting a section of text without rewriting the text itself. This type of “DNA formatting” is known as epigenetic marking.
The team analyzed the “format” of the POMC gene in more than 1,100 people and found more methyl groups attached to the satiety gene in obese women with a BMI greater than 35 than in women with normal body weight. “A 44% increase in the risk of obesity is more or less the same effect that has also been seen for individual genetic variants,” says Kühnen. “By comparison, socioeconomic factors have a much larger effect. They can increase the risk between two and three times.” As to why the methylation effect only appears in women, we don’t know yet.”
The POMC gene is “formatted” very early during embryonic development, as the researchers demonstrated by comparing methylation patterns in more than 15 sets of identical and fraternal twins.
While the “format” of the satiety gene was the same in most identical twins, there was little correlation in fraternal twins. “This indicates that epigenetic marking of the POMC gene is established soon after the egg and sperm fuse, before the fertilized egg divides into two twin embryos,” explains Lara Lechner, first author of the study. “This means that the earliest phase of pregnancy is crucial.”
Previous studies indicated that the presence or absence of certain nutrients that contribute methyl groups could have an effect on epigenetic processes.
But, What influences the methylation experienced by the satiety gene? and, therefore, in the risk of a person being overweight?
Previous studies indicated that the presence or absence of certain nutrients that contribute methyl groups could have an effect on epigenetic processes. Among these nutrients are betaine, methionine and folic acid, which are usually absorbed through the diet. A newly developed method using individual human stem cells allowed the Charité researchers to simulate in the laboratory how the methylation pattern is determined during embryonic development and how nutrients affect it.
“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,” says Kühnen. ‘We have observed that the ‘DNA formatting system’ is very stable as a whole, with cells compensating for small fluctuations in nutrient supply. For another, there are indications that the variability of this ‘formatting’ develops randomly. That means it’s not possible – not yet, in any case – to externally influence a person to have more or less methylation in the POMC region.”
The subjects 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.
In theory at least, women at increased risk of developing obesity due to POMC gene methylation could be given weight-loss drugs, as suggested by initial studies of four severely obese women and one man with this exact type of “formatting” of the satiety gene.
The subjects 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. Three months after starting treatment, all five patients experienced less hunger. They lost an average of seven kilograms, or about five percent of their body weight. Some of them continued treatment and continued to lose weight.
“These results show, for a start, that a POMC gene that has undergone epigenetic changes can be treated with medication,” says Kühnen. ‘Further large-scale controlled studies will be needed to show whether treatment with this drug would also be effective over a longer period and, if so, to what extent this type of treatment is effective and safe. In general, however, a drug like this would have to be just one piece of a comprehensive treatment strategy».
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