Friday, August 21, 2015

Metabolic switch

MIT, Harvard find 'master switch' behind obesity


Doctors may have found a way to override the body’s evolutionary habit of storing fat with a discovery of a master switch for the body’s metabolism.
According to a study published Wednesday in the New England Journal of Medicine, researchers from the Massachusetts Institute of Technology and Harvard Medical School discovered a new genetic pathway that controls human metabolism by prompting fat cells to store or burn away fat.
“Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism,” said senior author Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute, in a release.
Until now. Previous research had shown there was a strong association with obesity in the gene region known as FTO. Researchers started there, experimenting with more than 100 tissues and cell types, changing the genomic controls within that region to see if fat storage could be programmed independently of the brain.
Once researchers discovered evidence that there was a switchboard, researchers looked at fat tissue from Europeans with differing versions of the region, finding that those at risk for obesity had switchboards that turned on two distant genes — IRX3 and IRX5.
Further research into these genes showed that they act as master controllers of how fat cells either burn fat as release the energy as heat, or store it.
The discovery ultimately comes down to one letter nucleotide difference in these genes, which turns on these genes and ultimately turns off the body’s way of burning fat, leading to storage.
Changes in that one nucleotide changed the way the genes functioned, and made the cells burn energy instead of storing it.

“Knowing the causal variant underlying the obesity association may allow somatic genome editing as a therapeutic avenue for individuals carrying the risk allele,” Kellis said. “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 proved their findings in mice, by reprogramming the genes and finding that there was dramatic changes in body weight and fat storage, as well as a complete resistance to a high-fat diet.
“By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and the organismal level, providing new hope for a cure against obesity,” Kellis said.

The discovery is a promising start to ultimately finding a therapy for those who have the genetic code triggering fat storage. Researchers said they are partnering with other academics and industry partners to create obesity therapeutics, and are also using the approach to understand the circuitry of how other diseases might be tied into the human genome.