Unlocking the genetic ‘control switches’ of hibernation

Velentina Boulter – Velentina Boulter is science journalist based in Melbourne.

New research has identified specific regions of DNA that regulate hibernation by tweaking metabolism. The findings could offer pathways to new treatments for metabolic disorders like type 2 diabetes in humans.

When hibernating animals wake, they reverse dangerous health changes similar to those seen in type 2 diabetes, muscle atrophy, Alzheimer’s disease and stroke. Researchers hope that unlocking hibernation regions in the human genome could help develop treatments for these potentially fatal health conditions.

“If we could regulate our genes a bit more like hibernators, maybe we could overcome type 2 diabetes the same way that a hibernator returns from hibernation back to a normal metabolic state,” says Elliot Ferris, a bioinformatician at the University of Utah (U of U) Health in the US.

Ferris is co-author of 2 new studies which pinpointed that DNA regions near a gene cluster called the “fat mass and obesity (FTO) locus” play a crucial role in the ability to hibernate. While the FTO locus also appears in humans, hibernating animals use it in a different, and potentially more advantageous way.

“What’s striking about this [FTO] region is that it is the strongest genetic risk factor for human obesity,” says senior author of the study, Chris Gregg, a professor in neurobiology at U of U Health.

According to the World Health Organization, 1 in 8 people worldwide were living with obesity in 2022. Obesity can lead to an increased risk of type 2 diabetes, heart disease and other health implications, which illustrates the importance of preventing and treating the condition.

“Humans already have the genetic framework,” says Susan Steinwand, a research scientist at U of U and co-author of the studies. “We just need to identify the control switches for these hibernator traits.”

To locate the hibernation-specific regions of the genome, the team used multiple independent whole-genome technologies to compare mammals that do and don’t hibernate.

“If a region doesn’t change much from species to species for over 100 million years but then changes rapidly and dramatically in 2 hibernating mammals, then we think it points us to something that is important for hibernation, specifically,” says Ferris.

The hibernator-specific DNA regions (located close to the FTO locus) weren’t genes but DNA sequences called “cis–regulatory elements” (CREs) which contact nearby genes to either turn up or down their expression, almost like a film director coordinating cinematographers, set designers and actors. The researchers found the CREs regulated the activity of neighbouring genes, including those involved in metabolism.

When they mutated these regions in mice, the researchers observed changes in weight and metabolism. Some of the mutations the researchers performed sped up the weight gain, while others slowed it down. Other mutations affected the body’s ability to recover body temperature after hibernation.

They suggest that this is what allows animals to gain weight before entering hibernation and then slowly release the energy in their fat reserves during the winter.

This means that mutating a single hibernator-specific region has wide-ranging effects extending far beyond the FTO locus, says Steinwand.

“It’s pretty amazing,” she says. “When you knock out one of these elements – this one tiny, seemingly insignificant DNA region – the activity of hundreds of genes changes.”

The studies suggest that CREs might also play a role in regulating human metabolism.

While understanding this flexibility could lead to better treatments for disorders like type 2 diabetes, the study also helps indicate which DNA elements should be explored in future studies.

“There’s potentially an opportunity – by understanding these hibernation-linked mechanisms in the genome – to find strategies to intervene and help with age-related diseases,” says Gregg.

“If that’s hidden in the genome that we’ve already got, we could learn from hibernators to improve our own health.”

The research has been published in the journal Science.

Originally published by Cosmos as Unlocking the genetic ‘control switches’ of hibernation