The risk of obesity in women increases by 44 percent if a large number of methyl groups are attached to the (pro-opiomelanocortin) POMC gene, which has been linked to satiety. Further, a team from Charité—Universitätsmedizin Berlin, found that people with POMC epigenetic changes can respond to setmelanotide (Rhythm Pharmaceuticals’ Imcivree), which has already been approved to treat obese patients with a mutation of the POMC gene.
The team found more methyl groups attached to the satiety gene in women with a body mass index (BMI) of over 35 than in women with normal body weight, they also determined this epigenetic marking occurs early during embryogenesis.
This study was published July 19 in Science Translational Medicine. The lead author is Laura Lechner and the senior author is Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité.
People who are overweight are at increased risk of cardiovascular disease, diabetes, and cancer, among other conditions. It is a growing health issue. The World Health Organization reports that worldwide obesity has nearly tripled since 1975, and most of the world’s population live in countries where being overweight kills more people than being underweight.
Several factors, including socioeconomic status, lifestyle, and genetics are known to influence obesity risk. But even taken all together, the genetic variants associated with obesity cannot explain the heritability that has been observed. The similarity of BMI in identical twins, for example, ranges from 40 to 70 percent. Even identical twins raised in different families still show significant similarity. But genetic variants alone do not explain this.
Researchers suspected there must be additional non-genetic factors that affect a person’s propensity to gain excess weight. Epigenetic changes, unlike changes to DNA, “…are reversible and do not change your DNA sequence, but they can change how your body reads a DNA sequence,” according to the CDC.
For their study, the Charité researchers analyzed the “formatting” of the POMC gene in more than 1,100 people. They found that on average, more methyl groups attached to the satiety gene in obese women with a BMI of over 35 than in women with normal body weight. This also occurred in men, but at a much lower rate.
“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,” says 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,” he added.
The researchers also showed the POMC gene is “formatted” very early on during embryonic development, 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.
“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,” explains Lechner, who works at the Department of Pediatric Endocrinology. This means the very early stage of pregnancy is crucial.
In further study, five participants were given setmelanotide, which 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.
