Obesity ‘master-switch’ in genes may be turned off

The strongest genetic association with obesity lies within an unexpressed region of the FTO gene and contains 89 common variants in a region of 47,000 nucelotides. Dr. Clifford Rosen, scientist from the Maine Medical Center Research Institute and associate editor for the New England Journal of Medicine, gave a statement saying that the new findings are “a big deal”.

The researchers found that the rs1421085 T-to-C single-nucleotide variant in the FTO obesity-risk locus disrupted a conserved motif normally bound by repressor ARID5B.

A cure for obesity could be just an injection away after scientists at Harvard and MIT discovered that a tiny DNA tweak causes the metabolism to burn up excess fat.

The work solves a big mystery: Since 2007, researchers have known that a gene called FTO was related to obesity, but they didn’t know how, and could not tie it to appetite or other known factors. But “every human on the planet has that genetic circuit”, so researchers may be able to manipulate the IRX genes to eliminate obesity, he says.

The discovery challenges the notion that “when people get obese it was basically their own choice because they choose to eat too much or not exercise”, said study leader Melina Claussnitzer, a genetics specialist at Harvard-affiliated Beth Israel Deaconess Medical Center. “But an unbiased look across more than one hundred human tissues and cell types indicated that the obesity-associated region acts primarily in adipocyte progenitor cells – not the brain”. But some were obviously a lot heavier than that, and even 7 pounds can be the difference between a healthy and an unhealthy weight, said Manolis Kellis, a professor at MIT. Instead, the variant doubles the activity of two genes, IRX3 and IRX5, which are involved in determining which kind of fat cells will be produced. Fat tissue cells have been withdrawn from human respondents and the gene has been deactivated to see the triggering results.

A new study has finally revealed how the obesity gene, FTO, works and it’s helping experts understand how they can turn it off and how they can treat patients.

The researchers then sought to connect these differences in metabolism and gene expression to the genetic differences between lean and obese people within the FTO gene. Researchers also disrupted the IRX3 gene in fat cells of normal-weight mice. The animals’ metabolism increased and they lost weight, even though their physical activity and appetite were unchanged. What they learned is that the process caused by the faulty gene can be reversed. However, previous studies have failed to find a mechanism to explain how genetic differences in the region lead to obesity. Loss of repression turns on IRX3 and IRX5 during early adipocyte differentiation, leading to a shift from beige adipocyte functions and thermogenesis, or energy burning, to white adipocyte lipid accumulation. “This can serve as a model for understanding the mechanistic basis of other non-coding variants in other diseases and traits”. But researchers might use similar strategies to those in this study to figure out how genetic variants are linked to other diseases. “But more importantly, the uncovered cellular circuits may allow us to dial a metabolic master switch for both risk and non-risk individuals, as a means to counter environmental, lifestyle, or genetic contributors to obesity”.

Researchers used a new technology called the Crispr/Cas9 system to edit the DNA code and fix the sequence in mice and human cells.

This news could be revolutionary if such an injection comes to be developed.