Hibernating animals offer genetic clues to obesity, metabolic diseases

By studying squirrels and other hibernators, University of Utah scientists found new genetic clues about hibernation that they say could lead to better understanding and treatment of metabolic disorders such as obesity. (Marit & Toomas Hinnosaar/Flickr/CC BY 2.0)

Mammals that hibernate can put on a large amount of weight and still re-emerge as healthy as they were before. Now University of Utah scientists have identified genetic features related to this ability that they say could inspire new treatments for metabolic diseases such as obesity and Type 2 diabetes.

The secret of the development of hibernation lies in noncoding DNA regulatory elements linked to obesity-related genes, according to a study the team published in the journal Cell Reports.

“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,’” said co-author Christopher Gregg, Ph.D., assistant professor of neurobiology and anatomy at the University of Utah, in a statement.

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Gregg and colleagues previously studied the so-called accelerated regions of the genome, which are shared across vertebrate species but are amplified in certain animals to give them highly distinctive traits.

In a 2018 Cell Reports study, his team reported thousands of genetic elements that are conserved in the human genome and play potential roles in shaping clinically meaningful features. They delved into the elephant and found accelerated regions near a gene called Fancl—a key regulator of DNA repair—that helps the large animal manage mutations and cancer risk.

In the new study, Gregg and his team hypothesized there are obesity regulatory elements on accelerated regions that are different in hibernating mammals. The researchers picked four hibernating animals: the squirrel, little brown bat, lemur and tenrec.

After comparing their genomes, they discovered that these animals had indeed evolved with certain changes in parallel to conserved regulatory elements, which they called parallel accelerated regions. These regions on hibernators are disproportionately located near known human obesity susceptibility genes, they found. Those are genes implicated in Prader-Willi syndrome, a disorder marked by constant hunger and morbid obesity.

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The findings led Gregg's team to theorize that hibernators have developed methods for turning off specific genetic switches of obesity genes.

Metabolic disorders affect millions worldwide and have inspired several new treatment ideas. Another University of Utah team, in collaboration with scientists at Merck Research Laboratories, recently showed that shutting down the DES1 enzyme could reduce fatty lipids called ceramides, and hence reverse insulin resistance and fatty liver.

Other researchers have been examining gene therapies. A team led by Rejuvenate Bio co-founder and Harvard synthetic biology scientist George Church showed that delivering extra copies of longevity genes FGF21 and sTGF2betaR could treat mice with obesity, Type 2 diabetes, heart failure and kidney failure. And scientists at Hanyang University in Seoul used CRISPR interference to inhibit the FABP4 gene, which led to weight and reduced inflammation and insulin resistance in mice.

The University of Utah scientists figure their research lays a strong foundation for future studies to examine the 364 individual noncoding genetic elements that they have identified as contributors to obesity and other metabolic disorders. They are currently using CRISPR to swap in hibernator DNA sequences in mice to test for differences in gene expression.

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