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Formatting of DNA code in POMC gene implicated in risk of excess body weight

The formatting of the DNA code in pro-opiomelanocortin (POMC) gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight - at least in women. This “epigenetic marking” is established early on during the embryonic stage, according to a study by Charité – Universitätsmedizin Berlin, Germany.

Image: Neurons produced from human stem cells (red and green). The satiety gene POMC is active in cells marked orange. Blue: cell nuclei (Credit: Charité | lara lechner

Genetic predisposition plays a major role in obesity, alongside lifestyle. Scientists have identified several genetic variants that influence a person’s body weight – and with it, the risk of developing obesity. But even taken all together, they cannot explain the heritability that has been observed. Researchers began to suspect there must be additional non-genetic factors that affect a person’s propensity to gain excess weight.


Researchers led by Professor Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité, have now identified one such factor in their recent study. According to their findings, women’s risk of being overweight increases by about 44 percent if there are an especially large number of methyl groups adhering to the POMC gene, which is responsible for the feeling of satiety.


Methyl groups are tiny chemical units the body uses to mark the letters in the DNA code to activate or deactivate genes without modifying the sequence of letters in the DNA. In other words, the effect is much like highlighting a section of a text without rewriting the text itself. This type of “DNA formatting” is known as epigenetic marking.


For their study, the team of 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 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,” explained Kühnen. “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.”


The POMC gene is “formatted” very early on during embryonic development, as the researchers showed by comparing methylation patterns in more than 15 sets each of identical and fraternal twins. While the “formatting” of the satiety gene was the same in most of the identical twins, there was hardly any correlation in the fraternal twins.

Image: Neurons produced from human stem cells (red and green). The satiety gene POMC is active in cells marked orange. Blue: cell nuclei (Credit: Charité | lara lechner

“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,” added Lara Lechner, the study’s first author, who works at the Department of Pediatric Endocrinology.


This means the very early stage of pregnancy is crucial. But what influences how much methylation the satiety gene undergoes – and thus, the risk that a person will become overweight? Past studies indicated that the presence or absence of certain nutrients that supply methyl groups could have an effect on epigenetic processes. These nutrients include betaine, methionine, and folic acid, all of which are typically absorbed through a person’s diet. A newly developed method involving individual human stem cells allowed the Charité researchers to simulate in the lab how the methylation pattern is determined during embryonic development and how nutrients affect it.


“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,” noted 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 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.”

At least in theory, women who are at elevated risk of developing obesity due to methylation of the POMC gene could receive medications to help them lose weight, as initial studies of four severely obese women and one man with this exact type of “formatting” of the satiety gene suggest. The subjects were given a specific drug that curbs the feeling of hunger and has already been approved to treat obese patients with a mutation of the POMC gene. Within 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 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,” said 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.”

The findings were featured in the paper, ‘Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment’, published in Science Translational Medicine.

Image: Neurons produced from human stem cells (red and green). The satiety gene POMC is active in cells marked orange. Blue: cell nuclei (Credit: Charité | lara lechner

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