
Berlin, 20 July 2023
What determines whether we become obese? In addition to lifestyle, predisposition also has an effect, but genes cannot fully explain the inherited tendency to obesity. A study by the Charité – Universitätsmedizin Berlin in Science Translational Medicine* now shows that a kind of formatting of the DNA code of a satiety gene is also associated with a slightly increased risk of obesity – at least in women. This so-called epigenetic mark is already established in the early embryonic phase.
Obesity, especially severe obesity, increases the risk of a number of serious diseases such as cardiovascular disease, diabetes and cancer. The health problem is growing: worldwide, the number of overweight people is increasing; in Germany, it is assumed that two out of three men (60 percent) and just under half of the women (45 percent) weigh too many kilos.
But what determines whether people become overweight? One thing is clear: Besides lifestyle, predisposition plays a major role. In identical twins, the body mass index (BMI) is 40 to 70 percent similar. Even if they do not grow up in the same family, this great similarity remains. Several gene variants are now known to influence weight – and thus the risk of developing obesity. Taken together, however, they cannot explain the observed heritability. Researchers therefore suspected that there must be additional, non-genetic factors that affect the tendency to be overweight.
Saturation gene is not modified, but formatted
Researchers led by Prof. Dr. Peter Kühnen, Director of the Clinic for Paediatric Endocrinology at the Charité, have now identified such a factor in their current study. According to the study, the risk of obesity in women increases by about 44 percent if the gene POMC (proopiomelanocortin), which is responsible for the feeling of fullness, has a particularly large number of methyl groups attached to it. Methyl groups are small chemical units with which the body marks the letters of the DNA code to switch genes on or off without changing the DNA letter sequence. A comparison: the effect is similar to highlighting a section in a text without rewriting the text. This type of “DNA formatting” is called epigenetic marking.
For the study, the research team had analysed the “formatting” of the POMC gene in more than 1,100 people. In obese women with a BMI over 35, more methyl groups were found on the saturation gene than in normal-weight women. “An increase in the risk of obesity by 44 percent corresponds roughly to the effect that has also been observed in individual gene variants,” says study leader Prof. Kühnen. “In comparison, however, socioeconomic factors have a much stronger effect; they can increase the risk by two to three times. We don’t yet know why the effect of methylation only comes into play in women.”
The POMC gene is “formatted” very early in embryonic development, as the researchers demonstrated by comparing methylation patterns in more than 30 identical and fraternal twins each. While the “formatting” of the saturation gene matched in most cases in monozygotic twins, it hardly correlated in dizygotic twins. “This suggests that the epigenetic mark of the POMC gene is established shortly after the fusion of egg and sperm, even before the fertilised egg splits into two twin embryos,” explains Lara Lechner, first author of the study from the Department of Paediatric Endocrinology. So the very early phase of a pregnancy is already crucial.
What influences the formatting?
But what influences how strongly the satiety gene is methylated – and thus the risk of obesity? Past studies had suggested that the presence or absence of certain nutrients that serve as suppliers of methyl groups could potentially affect epigenetic processes. These nutrients include, for example, betaine, methionine or folic acid, which are usually ingested through food. A newly developed method has now enabled the Charité scientists for the first time to use individual human stem cells in the laboratory to mimic how the methylation pattern is determined during embryonic development and what influence nutrients have on it.
“On the one hand, our studies and others show that folic acid, betaine and other nutrients have a limited effect on the extent of methylation,” says Prof. Kühnen. “We have observed that the ‘DNA formatting system’ is quite stable overall and that minor fluctuations in the supply of nutrients are compensated for by the cells. On the other hand, there are indications that the variability of this ‘formatting’ develops randomly. This means that, at least currently, it is not possible to influence from the outside whether a person has more or less methylation in the POMC region.”
Drug help potentially possible
At least theoretically, women who have an increased risk of developing obesity due to a methylation of the POMC gene could be helped to lose weight with medication. This is indicated by initial results on four highly obese women and one man with precisely this “formatting” of the satiety gene. They received a specific active substance that intervenes in the development of the feeling of hunger and is approved for the obesity treatment of people with a mutated, i.e. faulty, POMC gene. Within three months of starting the treatment, the five patients felt less hungry and lost an average of seven kilograms, or about five percent of their body weight. Some of them continued the treatment longer and lost more weight.
“These results show first of all that an epigenetically altered POMC gene can potentially be addressed with drugs at all,” says Prof. Kühnen. “Further large controlled studies must show whether and how effective and safe the treatment with the active substance would also be over a longer period of time. Overall, however, such a drug could only be part of a comprehensive treatment strategy.”
*Lechner L et al. Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment. Sci Transl Med 2023 Jul 19. doi: 10.1126/scitranslmed.adg1659
About the study
Study leader Prof. Dr. Peter Kühnen is Director of the Clinic for Paediatric Endocrinology at the Charité. For his work on normalising body weight, the Heisenberg professor received the Paul Martini Prize in 2020, which is endowed with 50,000 euros. The current study was carried out within the framework of a Consolidator Grant from the European Research Council (ERC), which Prof. Kühnen obtained to investigate the role of epigenetic variability in the development of metabolic and endocrine diseases (E-VarEndo). The work was also funded by the German Research Foundation, the SPARK-BIH programme of the Berlin Institute of Health at the Charité (BIH) and a BIH doctoral scholarship.
Figure: Nerve cells produced from human stem cells (red and green). The saturation gene POMC is active in cells marked in orange. Blue: cell nuclei. © Charité | Lara Lechner