The number of overweight people has increased drastically in recent years in an epidemic of obesity. By measuring the minute chemical changes on the surface of people’s DNA, researchers can predict whether a person is at risk of developing a metabolic disease in the long term
Deep down, most of us know that our lifestyles can make us ill. Nevertheless, more and more of us are plagued with obesity and related diseases such as type 2 diabetes. Researchers can now measure that changes in lifestyle directly influence our genes and thereby our metabolism.
“Our research shows that, even in the short term, overeating can lead to minute chemical changes in DNA. These are called epigenetic modifications and regulate how genes are expressed,” explains Linn Gillberg, who co-authored a new study with Rasmus Ribel-Madsen.
The research was carried out at the Department of Endocrinology at Rigshospitalet in Copenhagen with the Danish Diabetes Academy co-funding the research. The researchers recently published their results in Clinical Epigenetics. These show that body mass index (BMI) is associated with epigenetic modifications. The study took samples of blood and subcutaneous fat (fat under the skin) and muscle biopsies from 137 first-degree relatives of people with type 2 diabetes.
A blood test can detect obesity and diabetes
The researchers were especially interested in how many methyl groups there are in a specific region of the HIF3A (hypoxia-inducible factor 3 alpha subunit) gene and whether the degree of methylation is important in determining the level of gene expression.
“Previous studies have shown that mice that lack this gene in their subcutaneous fat are more resistant to weight gain and are not resistant to insulin, which people with type 2 diabetes are. Based on the data from previous studies, we wanted to investigate whether methylation and gene expression of HIF3A in blood, subcutaneous fat and muscle tissue could indicate whether people become obese or develop type 2 diabetes,” explains Linn Gillberg.
The DNA methylation of a specific gene normally differs from tissue to tissue. Several research groups have recently become interested in HIF3A because its epigenetic modifications in blood and subcutaneous fat are associated with a person’s BMI. The researchers at Rigshospitalet also discovered that the participants’ expression of HIF3A in subcutaneous fat was associated with insulin sensitivity.
“Fatty tissue is a key regulator of blood glucose, and the HIF3A gene shows the direct effect of the epigenetic modification in fatty tissue on blood cells. This opens up the possibility for a general practitioner to give a patient a blood test that investigates epigenetic markers. In the long term, epigenetic analysis can be used for clinical risk assessment,” explains Rasmus Ribel-Madsen.
New light on genetics and the environment
Epigenetics integrates the discussions on genetics and the environment because much evidence indicates that epigenetic signals such as methylation of DNA not only are affected by genes but also by the environment, diet and lifestyle. Such genes as HIF3A are especially biologically interesting because they are activated when cells are oxygenated less than normal, which they are in the enlarged fat cells in the fatty tissue of obese people.
“Our research group recently published a study on fat stem cells. This shows that maternal environmental factors can cause epigenetic modifications before birth and that these modifications in individual adults continue to affect the capacity of cells to develop into fat cells that can store fat appropriately when needed. This can partly explain why some people can live healthily with large fat deposits whereas others are at risk of metabolic diseases,” adds Rasmus Ribel-Madsen.
However, this new study of HIF3A does not explain the causal relationships between obesity, methyl groups, gene expression and insulin sensitivity. Several studies are therefore being planned in which researchers can directly link experimental diets and exercise programmes with changes in the degree of methylation and gene expression.
“Our intervention studies are quite unique, since we can combine tissue biopsies and blood tests with detailed investigations of how the human body metabolizes sugar and fat. We can therefore create new knowledge within this specific field and thus help to combat the epidemics of obesity and type 2 diabetes,” concludes Rasmus Ribel-Madsen.
Clinical Epigenetics published the article "DNA methylation and gene expression of HIF3A: cross-tissue validation and associations with BMI and insulin resistance". The Novo Nordisk Foundation awarded project funding to the Department of Endocrinology of Rigshospitalet from 2011 to 2015 for research into epigenetic mechanisms.