Variation in genetic mechanism increases fat storage and drives obesity

A specific gene region has long been suspected of contributing to obesity in humans but the precise mechanisms behind this were previously unclear. Now, researchers at the Technical University of Munich (TUM), Massachusetts Institute of Technology (MIT), Harvard Medical School and other partners have been able to show that a single genetic alteration in this region reduces thermogenesis (fat burning), instead increasing lipid storage. Their study appears in the New England Journal of Medicine.

More than 500 million people worldwide suffer from obesity, including around 15 million in Germany. But what part does individual genetic makeup play?

In 2007, a region within a gene – known as the FTO gene – was identified as the key genetic candidate associated with obesity. People carrying this region had an increased risk of becoming overweight. Until now, though, the mechanism behind this link between the gene region and obesity could not be determined.

With the aid of the Roadmap Epigenomics Project, the researchers first used bioinformatic methods to establish the tissue types in which the FTO region was most active or actually showed epigenetic alteration – a sign of particular genetic activity. Their findings were surprising. Dr. Melina Claussnitzer, TUM researcher and first author for this study explained:

Many studies have tried to link the FTO region with areas of the brain controlling appetite or propensity for physical activity. We have now been able to show that the regulatory region within FTO has the greatest impact on adipocyte (or fat cell) progenitors, independent of circuits in the brain.”

This led the researchers to suppose that process dysregulation in these upstream progenitor cells could be responsible for the development of obesity. They examined samples of human fat tissue taken from participants carrying either the normal or the risk region of the FTO gene. The outcome was that two specific genes – IRX3 and IRX5 – were only expressed in the risk group.

Prof. Hans Hauner, Chair of Nutritional Medicine at TUM, who was involved in the study, adds:

As far as we were concerned, this was a highly significant finding. Further experiments showed that IRX3 and IRX5 activate a process that causes the progenitor cells to develop into fat storage cells and lose the ability to burn fat. This effect evidently changes the energy balance and can contribute to obesity.”

Once the researchers had understood the process, they were also able to selectively influence it. If they initiated IRX3 or IRX5 expression in cultures with human fat cell progenitors, the cells activated lipid storage. If, on the other hand, both genes were inactive, the cells burned fat and generated heat. The team was then also able to confirm these findings in animal experiments. Mice with IRX3 inhibited in fat cells displayed a higher metabolic rate and did not gain weight even on a high-fat diet.

The researchers then went even further, revealing not only the mechanism but also the exact genetic cause in their study. They identified a single area of the FTO gene region that was altered in the risk variant. If the researchers then used the latest genetic engineering methods to repair this defect in human fat cells, they functioned normally again, increasing fat burning and heat generation instead of lipid storage.

Melina Claussnitzer compares this detection of the link between FTO and obesity to investigating a crime. “The prime suspect, FTO, turns out not to be the actual perpetrator. Our new methods have now convicted two offenders, IRX3 and IRX5, originally not under suspicion.”

She adds: “Our biggest challenge was identifying three things: the instrument of crime – that is, a genetic variation in an elusive region – the scene of the crime, i.e. fat cell progenitors, and the facts of the case in terms of inhibited fat burning.”

This meant developing a new methodology, which called for intensive efforts on the part of Claussnitzer and the study’s final author, MIT Professor Manolis Kellis. The two TUM and MIT researchers are now applying this fresh approach to a wide range of other diseases in collaboration with MIT and Harvard Medical School.

“There are thousands of genetic associations within the genome that have been linked to the most diverse diseases. Yet the mechanisms behind this remain completely unknown, since they are localized in genomic regions that do not code for proteins and were even dubbed “junk” in the past. Our method serves as a model to accelerate studies involved in decoding genetic signals in the future. This could pave the way for personalized medicine for obesity or type-2 diabetes,” concludes Claussnitzer.