Obesity rates have quadrupled worldwide since the 1980s, making it one of the biggest health concerns of our time. This complex disease is closely linked to the leading causes of death worldwide, including heart disease and stroke resulting in the loss of approximately 22.9 million lives each year, about the population of New York City.

Variations in our genetic code alone do not explain the sharp increase in obesity over recent decades. We now understand that interactions between our genes and our environment can cause modifications to DNA. These modifications affect how our body interprets signals to switch genes on or off and is a growing field of study known as epigenetics. What makes these epigenetic switches particularly promising is their reversibility, opening the door to potential therapeutic interventions.

One well-studied epigenetic switch, DNA methylation (the addition to DNA of a ‘methyl’ group comprising one carbon and 3 hydrogen atoms), has received considerable attention. DNA methylation can switch genes on and off, however, previous attempts to establish whether DNA methylation has a causal role in human obesity have proved inconclusive.

Now a team, led by the MRC LMS Genomics of Obesity Group, conducted a study comparing the fat cells of individuals with extreme obesity to those with a healthy body weight. This research, published in Nature Comms, discovered a staggering 864 DNA methylation sites that were switched on or off in the fat cells of people with extreme obesity. They also found more than 500 genes that were changed by the DNA methylation switches in people with obesity but not those with a healthy body weight.

‘This research has the potential to revolutionise our understanding and treatment of obesity. We are getting closer to personalised and effective treatments as we unravel the complex connections between our DNA and our health.’

– Damir Baranašić, researcher in the MRC LMS Computational Regulatory Genomics group

Using cutting-edge computational techniques with the MRC LMS Computational Regulatory Genomics Group the researchers showed that a large proportion of these DNA methylation switches were critical determinants of obesity and its main complication, type 2 diabetes. They further revealed the significance and mechanisms of these DNA methylation sites using the gene editing technology CRISPR in fat cells.

Damir Baranašić, researcher in the MRC LMS Computational Regulatory Genomics group, stated,

“This work, led by Will Scott, is a testament to the power of collaborative efforts in our Institute. This research has the potential to revolutionise our understanding and treatment of obesity. We are getting closer to personalised and effective treatments as we unravel the complex connections between our DNA and our health.”