Epigenetic changes in a particular gene that controls satiety can increase the risk of becoming overweight, according to a study published in Science Translational Medicine. The researchers from Charité – Universitätsmedizin Berlin found that this epigenetic marking is established during the early stages of embryonic development.
People who are overweight have an increased risk of developing a variety of medical conditions, such as cardiovascular disease, diabetes, and cancer. According to the World Health Organisation, about two out of three adults are overweight, and the number is expected to rise in the future.
But researchers still don’t know why some people seem more prone to becoming overweight. Researchers know that lifestyle and genetic predisposition play a major role, but these factors cannot explain everything. In the past few years, researchers started to suspect there must be additional non-genetic factors that affect a person’s propensity to gain excess weight.
To solve this mystery, a team from Charité – Universitätsmedizin Berlin analysed the “formatting” of the POMC gene (a gene that controls feeling full after eating) in more than 1,000 participants in the study. They found more methyl groups attached to the satiety gene in obese women with a BMI over 35 than in women with normal body weight. “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,” said Prof. Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité. “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.”
In addition, the team also showed that the POMC gene is “formatted” very early during embryonic development. For this, they compared methylation patterns in more than 15 sets of identical and fraternal twins. The changes were similar for identical twins, but there was no correlation for 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,” explained Lara Lechner from the Department of Pediatric Endocrinology. This means the very early stages of pregnancy are crucial for this process.
There’s still the question of what influences these methylation patterns. Some studies have suggested that some nutrients can supply methyl groups to promote this epigenetic process, but the current study seems to indicate that it is more of a random process and cannot be influenced externally. “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,” explained Kühnen. “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 this ‘formatting’ variability 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.”
The good news is that medications may be able to counteract the effect of this gene. Five severely obese patients with this exact type of “formatting” managed to lose weight and feel less hungry when given medication to counteract the effects of the POMC gene. They lost an average of seven kilograms, and they stayed with the treatment and continued to lose weight. “These findings show, for a start, that a POMC gene that has undergone epigenetic changes can, in fact, potentially be addressed through medication,” concluded 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 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.”
Lechner L et al (2023) Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment.Sci. Transl. Med.15,eadg1659, 10.1126/scitranslmed.adg1659