"The obesity gene": correcting mistakes

Using modern DNA editing techniques, the team of researchers found that it is possible to change the activity of genes that affect metabolism and body weight.

It turned out that a certain variant of the well-known "obesity gene" affects metabolic processes and determines whether the cell will burn energy or store it in the form of fat reserves. This discovery may lead to the fact that one day doctors will be able to offer patients with "genetic" obesity therapy that will permanently rid them of this predisposition.

According to researchers from the United States, the genetic basis of the tendency to fullness quite strongly affects weight gain. One of the genes with the strongest and most stable association with obesity is called FTO. People with certain versions of this gene tend to be more overweight than others and are more likely to develop obesity.

However, no one has previously been able to understand how this gene works in cells and how this work affects the body as a whole. It was believed that FTO controls the work of other genes, but it was quite problematic to fully prove this.

Now Melina Claussnitzer, Manolis Kellis and their colleagues from the Massachusetts Institute of Technology have found an explanation. They turned to the Roadmap Epigenomics Project database, which describes the chemical "tags" on DNA responsible for the functioning of genes. The researchers used these epigenetic tags to determine whether the FTO gene was active or inactive in each of the 127 cell types.

As the researchers say in a press release (A metabolic master switch underlying human obesity), the FTO gene was active inside developing fat cells, the so-called adipocyte progenitor cells.

After that, the scientists checked the activity of eight genes that were previously thought to be linked and possibly controlled by the FTO gene. The material for the analysis was taken from healthy Europeans who are not obese. It turned out that about half of the volunteers were carriers of the version of FTO that is associated with obesity, as well as two other genes – IRX3 and IRX5 – that were present in their body cells, unlike people who did not have a specific version of FTO.

In their article (Claussnitzer et al., FTO Obesity Variant Circuitry and Adipocyte Browning in Humans), published in the New England Journal of Medicine, scientists explain that this pair of genes, IRX3 and IRX5, controlled by the FTO gene, is most likely responsible for what kind of fat cell the cell should turn into-the predecessor.

Excessive activity in the IRX3 and IRX5 genes prompts the developing cell to become a white adipocyte, which stores energy in the form of fat. Lower levels of activity of these genes are associated with the formation of so-called brown adipocytes, which use energy to produce heat.

The specific version of the FTO gene associated with obesity most likely cannot suppress the activity of the IRX3 and IRX5 genes, and therefore the formation of excess white adipose tissue begins.

The researchers conducted an experiment with adipocyte progenitor cells, during which they used the famous DNA editing technique called CRISPR-Cas9. They tried to switch the FTO gene inside the cells, replacing its obesity-associated version with a healthy one. The treated cells showed a decrease in the activity level of the IRX3 and IRX5 genes, as a result of which more brown and fewer white adipocytes began to form.

In the near future, scientists plan to conduct experiments on animal models, and then clinical trials of gene therapy. Nevertheless, doctors have yet to understand whether this technique is suitable for the treatment of a genetic tendency to obesity. However, if a person suffers from overweight due to psychological characteristics, then in any case he will not lose weight thanks to the discovery of MIT specialists.

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20.08.2015