Dormant hibernation genes in humans could unlock treatments for metabolic diseases 

Animals that hibernate exhibit extraordinary resilience, surviving for months without food or water, while maintaining muscle mass, lowering body temperature to near freezing while significantly reducing metabolic and neurological activity. Upon emerging from their hibernated state, they recover from physiological conditions that are analogous to type 2 diabetes, Alzheimer’s disease and stroke.

A recent study published by researchers at University of Utah (U of U) Health has suggested that the genetic mechanisms responsible for these traits may already exist dormant within human DNA. Their findings have provided fresh insight into how to alter gene regulation to potentially reverse neurodegeneration and metabolic dysfunction.

The research focused on a gene cluster known as the fat mass and obesity-associated (FTO) locus, which plays a key role in the metabolic adaptations seen in hibernating animals. This region is also the strongest known genetic risk factor for obesity in humans. However, the study found that hibernators are able to regulate genes in and around the FTO locus in ways that confer distinct physiological advantages.

The team identified non-coding, hibernator-specific DNA elements located near the FTO locus. These sequences act as regulatory switches, modulating the activity of adjacent genes to support energy storage and thermoregulation. Mutations introduced into these regulatory elements in mouse models led to measurable changes in weight gain, fat metabolism and the ability to restore body temperature following torpor-like states.

“These regions are not genes themselves, but they influence gene expression,” said Susan Steinwand, a research scientist in neurobiology and anatomy at U of U Health and first author on one of the studies.

“When we removed one seemingly insignificant DNA element, the activity of hundreds of genes shifted. It was astonishing,” she added.

The researchers observed that the majority of hibernator-specific DNA alterations appeared to remove constraints on metabolic control rather than introduce novel functions. This suggests that hibernators may have evolved an enhanced ability to modulate energy use by eliminating fixed genetic restrictions.

Humans, by contrast, may retain a ‘locked’ metabolic thermostat within a narrower operating range.

To narrow down relevant regions of the genome, the researchers employed a combination of comparative genomics and gene-expression profiling. They first looked for regions conserved across mammals that had diverged rapidly in hibernating species. These were then cross-referenced with gene activity changes observed during fasting in mice, a condition that mimics aspects of the physiology of hibernation.

“When a DNA region remains unchanged across species for over 100 million years and then shifts dramatically in just two hibernating species, it likely plays a role in hibernation,” explained Elliott Ferris, a bioinformatician and first author of a companion study.

By mapping interactions between these altered DNA elements and key regulatory ‘hub’ genes, the team has created a shortlist of candidate control regions for future therapeutic targeting.

“If we could learn to regulate our genes like hibernators do, we might one day be able to reverse conditions such as type 2 diabetes,” said Ferris.

The findings support the hypothesis that humans already possess a latent genetic architecture similar to that of hibernators.

“There is potentially an opportunity to use these insights to develop interventions for age-related diseases. If these mechanisms are encoded within our genome, then hibernators could help us to unlock a novel approach to human health,” added Professor Chris Gregg, senior author and professor of neurobiology, anatomy and human genetics at U of U Health.

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Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioural Adaptations in Mice

Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus