Cutting genes, rather than calories, may be a new way to lose weight, new Yale research suggests.

The study, published in the August 3 issue of the journal Cell Metabolism, suggests that reduced expression of the so-called “I’m Not Dead Yet” or INDY gene in the liver protects against obesity and type 2 diabetes in a manner similar to calorie restriction. But scientists have so far only produced this effect in flies, worms and mice, said lead author and School of Medicine postdoctoral fellow Andreas Birkenfeld.

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“Genetic manipulations are difficult in human subjects from different points of view,” said Birkenfeld. “But we think that it might be a promising approach to target the INDY gene product, the INDY transporter, with a compound against obesity, fatty liver disease and type 2 diabetes.”

The study is the first time that the INDY gene — which is associated with the way the body stores and uses energy — has been shown to affect metabolism in mammals. The researchers engineered a mouse with the INDY gene deleted, and observed an increased breakdown of fatty acids and improved cellular energy transport, Birkenfeld said. Metabolism in the liver was key, he added, because the liver produces and stores glucose and lipids, which can affect the body’s generation of biochemical energy.

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“In pathological conditions such as obesity and type 2 diabetes, these processes become progressively disregulated, most likely because the liver is overwhelmed with dietary fat,” Birkenfield said. “Therefore, interventions that help the liver to get rid of extra fat also help to improve whole body energy balance, and in turn insulin resistance to type 2 diabetes.”

But deleting the INDY gene in subjects is not a silver bullet for curing weight related illnesses.

Genetic modification might only be beneficial as long as individuals do not have dietary deficits, said School of Medicine scientist Michael Jurczak. In certain conditions, such as starvation, it may in fact be favorable for organisms to have the INDY gene.

Meanwhile, scientists have no evidence suggesting that removing the INDY gene would have an effect on patients with type 1 or chronic diabetes, and no way of knowing precisely how much a subject’s metabolism would be boosted. Mimicking calorie restriction through genetic means, he said, may also not be the best prescription for fighting diabetes and obesity.

“Proper diet and exercise are the cornerstones of a healthy lifestyle,” Jurczak said. “These interventions are always the first to be recommended to diabetic individuals.”

The researchers are now studying the INDY gene and its significance in human metabolism more closely, Birkenfeld said. If successful, they may find a way to prolong an individual’s lifespan by delaying the diseases that come with aging.

The gene is named INDY in homage to a line from Monty Python and the Holy Grail, in which a supposed plague victim protests, “I’m not dead yet!” while he is hauled off for burial, still alive.


In an earlier version of this story, the titles of Andreas Birkenfield and Michael Jurkzak were incorrect. Birkenfield was a Postdoctoral Fellow at Yale and Jurkzak is an Associate Research Scientist.