The study, co-authored by scientists at MIT and the Harvard University Medical School, appears in the New England Journal of Medicine.
Advertisement
The researchers predicted that a genetic difference of only one nucleotide is responsible for the obesity association. Affecting more than 500 million people worldwide, obesity costs at least $200 billion each year in the United States alone, and contributes to potentially fatal disorders such as cardiovascular disease, type 2 diabetes, and cancer.
FTO’s intron is an enhancer, a stretch of DNA needed to control activity of far-away genes, the researchers discovered. 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.
“Previous studies attempted to uncover a link between FTO and the regulation of appetite or propensity to exercise controlled by the brain”, said the study’s lead and corresponding author Melina Claussnitzer, PhD, an investigator in the Division of Gerontology at BIDMC and Hebrew SeniorLife, visiting professor at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and member of the Broad Institute. That result indicates that the white-to-beige fat switch works in fat tissue, not in 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. They found that the risk version activated a major control region in adipocyte progenitor cells, which turned on two distant genes, IRX3 and IRX5. The wrong code was causing genes IRX3 and IRX5 to turn on when they should have been off. Disruption also resulted in a cell-autonomous developmental shift from energy-dissipating beige adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis and increase in lipid storage. However, they are only meant to be used short-term and manipulate brain and appetite, rather than target metabolism.
The research strongly suggests that 44 percent (44%) of obese people may not have had a choice at all, and that their genes made them this way, just like they gave them green, blue or brown eyes. Moreover, their body continued to burn energy even when they were asleep, revealing more interesting facts about the functioning of the FTO gene.
The FTO gene turns out to influence obesity indirectly, as a master switch that affects two other genes that control thermogenesis, or burning off energy.
“We could narrow down a genetic region spanning 47,000 nucleotides to reveal a single- nucleotide adjustment, and explain precisely how it leads to loss of repressor binding, activation of a regulatory region, gain of distal gene expression, a change in adipocyte metabolism, and ultimately obesity at the organism level”, explained Claussnitzer. What they learned is that the process caused by the faulty gene can be reversed. “Non-coding variants make up more than 90 percent of top-scoring variants that have emerged from genome-wide association studies, which find association between genetic variants and disease risk”.
“Knowing the causal variant underlying the obesity association may allow genome editing as a therapeutic avenue for individuals as risk”.
Advertisement
Researchers used a new technology called the Crispr/Cas9 system to edit the DNA code and fix the sequence in mice and human cells. But there’s hope as the new findings may open the door to developing meds that can get fat cells to behave differently.
