Epigenetics determines which subtype of obesity people have

Breaking new ground 16. okt 2022 3 min Research manager Allan Vaag Written by Kristian Sjøgren

Researchers have identified two subtypes of obesity that are determined by epigenetics. A researcher says that because the subtype of obesity is probably determined during fetal development, preventive measures should already be put in place at this stage.

Researchers have for the first time characterised two subtypes of obesity, each with its own physiological and molecular presentation. This provides evidence of epigenetics playing a role not only in the risk of developing obesity but also in the subtype of obesity.

One subtype of obesity has increased fat mass. The other has increased fat mass, increased muscle mass and increased levels of inflammatory markers in the blood.

Overall, the research results indicate that epigenetics play a role in determining whether obesity is relatively harmless, or whether, through inflammation, it is associated with an increased risk of developing cancer and cardiovascular diseases.

“Because epigenetics seems to have this effect, the source of the development of obesity and the subtype is most likely rooted already during fetal development. We envision that some environmental factor affects the epigenetics of the fetus, with consequences for an individual’s metabolic profile for the rest of their lives,” explains a researcher behind the study, Allan Vaag, Consultant and Professor, Steno Diabetes Center Copenhagen and Lund University, Sweden.

The research, which was led by Andrew Pospisilik, Professor, Van Andel Institute, Grand Rapids, Michigan, USA, has been published in Nature Metabolism.

Monozygotic twins are identical but not completely

The researchers studied blood samples, adipose biopsies and other data from twin pairs in the United Kingdom and Denmark. Allan Vaag provided data and samples from the twin pairs in Denmark.

The researchers investigated whether they could identify metabolic subtypes that affect differential appearances among the twin pairs.

They found that the test participants could be divided into four groups: two groups had normal weight and two groups had obesity.

The two groups with obesity also differed in their physiological and molecular profiles.

Allan Vaag explains that this indicates that there are two unique subtypes of obesity, each of which provides its own risk to health. One subtype appears to be significantly more unhealthy than the other, since it is associated with more inflammation, which in turn is known to be associated with an increased risk of developing various diseases.

Altered epigenetic contact

The researchers also found other differences between the two groups with obesity.

The group with higher levels of inflammatory markers in the blood also had increased levels of insulin in the pancreas and decreased levels of neuronatin in tissue. Neuronatin is associated with epigenetic alterations, and reduced neuronatin levels are thought to represent a main cause of the identified differences.

To understand the significance of these lower levels of neuronatin, the researchers investigated the effect of low levels of neuronatin in mice.

They found that this increased the likelihood of epigenetic alterations towards a more unhealthy metabolic profile – exactly what the researchers had found in the twin studies.

The researchers also found that neuronatin is involved in controlling an epigenetic regulatory mechanism that can be switched on or off. With low levels of neuronatin, there was an increased likelihood of the switch being activated and causing the unhealthy subtype of obesity or not being activated at all. With high levels of neuronatin, the switch was harder to activate and the risk of the unhealthy subtype of obesity was thus lower. There was no overlap between the two subtypes: either one or the other.

“Epigenetics seems to make the switch to the unhealthy obesity subtype easier when the body lacks neuronatin. The interesting thing therefore is to investigate why an individual may lack neuronatin ,” says Allan Vaag.

Increased insulin leads to developing obesity

In follow-up studies, the researchers also found that mice with the unhealthy subtype of obesity had elevated levels of insulin in their pancreas.

This indicates that neuronatin, epigenetics, increased insulin production in the pancreas and obesity may be linked. Indeed, it is known that elevated insulin is associated with an increased risk of developing obesity.

“This also indicates that genetics cannot explain the development of this subtype of obesity. Epigenetic differences seems to be the decisive factor, and this is new,” explains Allan Vaag.

Opportunity for earlier treatment

Allan Vaag sees clinical potential in the new discovery since epigenetic control of the genes is usually established during fetal development.

This means that epigenetic changes can occur during fetal development, so that even identical twins with exactly the same genes have different risks of developing diseases associated with obesity. Allan Vaag and his group already many years ago demonstrated that among genetically identical twin pairs in which only one twin has type 2 diabetes, the twins without diabetes had both relatively higher weight at birth and less obesity in adulthood. Thus, Allan Vaag thinks that identifying what happens during fetal development will be useful, since this may affect a person’s weight profile for the rest of their lives. Determining when this occurs will also be relevant.

Allan Vaag envisions that the explanation could be a hormone-disrupting substance or a dietary factor that affects epigenetic control during fetal development.

Identifying both the cause and the time of the changes may enable interventions that can alleviate the problem.

“The development of obesity does not just result from excessive food and unfortunate genes but also from how the genes are regulated epigenetically. This is expressed throughout life, but the starting-point is fetal development,” says Allan Vaag.

He also thinks that developing methods to rapidly investigate which subtype of obesity people have can provide much more personalised treatment.

“Preventive treatment can start much earlier and target the results of epigenetics,” concludes Allan Vaag.

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