Many mammals gain weight and become insulin resistant during fall. However, these changes are easily reversible, and the mammals will not develop any further unhealthful symptoms. Researchers believe that the explanation for this lies in mechanisms associated with hibernation.

Researchers have recognized the fact that a wide array of animals have "superpowers."

Specifically, the same conditions that affect humans—some of which can be life threatening—may not affect animals at all.

Two such examples are elephants and whales, whose cancer risk is practically zero. Other animals are unlikely to develop metabolic conditions such as obesity. Why is this?

Researchers Elliott Ferris and Christopher Gregg, from the University of Utah in Salt Lake City, believe that hibernation may have something to do with it.

Many mammals around the world hibernate in the cold season. Hibernation is characterized by entering a sleep-like state in which body temperature drops, breathing slows down, the heart beats more slowly, and all other metabolic (automated, self-regulating physiological processes) slow down.

This allows hibernating animals to survive during the winter months, when food becomes scarce and living conditions less friendly.

As Ferris and Gregg note in their new study paper in the journal Cell Reports, many hibernating animals actually put on a lot of weight in the buildup to hibernation. They also become insulin resistant.

These are two aspects characteristic of obesity. However, in hibernating animals, they mean only that the animals are able to access a timely reserve of fat during the winter months.

Unlike when humans develop obesity, hibernators can later easily shed the extra weight, and their bodies automatically reverse insulin resistance. Also, unlike humans with obesity, hibernating mammals do not develop hypertension or low-grade inflammation, both of which could lead to further health concerns.

For these reasons, Ferris and Gregg believe that some genetic mechanisms involved in regulating hibernation may also play a role in obesity control.

Prodding the secrets of noncoding DNA

"Hibernators have evolved an incredible ability to control their metabolism," explains Gregg, an associate professor in the Department of Neurology & Anatomy at the University of Utah.

"Metabolism shapes risks for a lot of different diseases, including obesity, type 2 diabetes, cancer, and Alzheimer's disease," he adds. "We believe that understanding the parts of the genome that are linked to hibernation will help us learn to control risks for some these major diseases."

"A big surprise from our new study is that these important parts of the genome were hidden from us in 98% of the genome that does not contain genes—we used to call it 'junk DNA,'" says Gregg.

For their new study, Gregg and Ferris analyzed the genomes of four hibernating mammalian species: the 13-lined ground squirrel, the little brown bat, the gray mouse lemur, and the lesser hedgehog tenrec.

When comparing the genomes of these species, the researchers found that they had all evolved—on an independent basis—a series of short DNA sections called "parallel accelerated regions."

Accelerated regions also exist in humans, though scientists understand very little about them. What researchers know so far is that accelerated regions feature noncoding DNA, and that they did not change much as mammals evolved through the ages.

Except in humans, that is, in whom they suddenly started changing and shifting around the time that we split from our primate "cousins."

After further analyzing the data, the researchers noticed that parallel accelerated regions appear close to genes linked with obesity in humans.

To confirm the link between accelerated regions and genes that play a role in obesity control, Gregg and Ferris then analyzed a very specific set of genes: those that drive Prader-Willi syndrome, a rare genetic condition in humans.

Among other symptoms, this condition is characterized by an excessive appetite, which can lead to unhealthful weight gain and obesity.

In looking at the genes linked to Prader-Willi syndrome, the researchers did find that these genes are associated with more hibernator accelerated regions when compared with genes that did not play a role in this genetic condition.

'Laying foundations for new research'

Following these results, Gregg and Ferris now suggest that hibernating animals may have evolved mechanisms that allow them to automatically "switch off" the activity of certain genes associated with obesity. This is not the case for nonhibernating mammals.

The investigators also identified as many as 364 genetic elements that may help both regulate hibernation and control obesity.

"Our results show that hibernator accelerated regions are enriched near genes linked to obesity in studies of hundreds of thousands of people, as well as near genes linked to a syndromic form of obesity," says Ferris.

"Therefore, by bringing together data from humans and hibernating animals, we were able to uncover candidate master regulatory switches in the genome for controlling mammalian obesity," he adds.

Using specialized gene editing technology, the researchers are currently testing the role of these 364 genetic elements in mouse models. They hope that their findings will eventually help them find a way of controlling not just obesity, but also other conditions related to metabolic mechanisms.

"Since obesity and metabolism shape risks for so many different diseases, the discovery of these parts of the genome is a really exciting insight that lays foundations for many important new research directions. We have new projects emerging for aging, dementia, and metabolic syndrome."

Christopher Gregg