Study of Hibernating Animals, PWS Patients Reveals Over 300 Potential Genetic Regulators of Obesity

Study of Hibernating Animals, PWS Patients Reveals Over 300 Potential Genetic Regulators of Obesity
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A genetic analysis of hibernating animals and people with Prader-Willi syndrome (PWS) has revealed more than 300 small genetic sequences that may regulate fat accumulation and obesity, a study reports.

This discovery adds new knowledge on the underlying processes of fat buildup and reveals new clues on potential genetic factors that may contribute to rare obesity and metabolic disorders, such as PWS.

These findings resulted from the study, “Parallel Accelerated Evolution in Distant Hibernators Reveals Candidate Cis Elements and Genetic Circuits Regulating Mammalian Obesity,” which was published in the journal Cell Reports.

Accumulation of fat during the spring and summer is an important adaptive mechanism for mammals to survive the colder seasons. This behavior is particularly important for hibernating mammals, which accumulate fat to support their body needs during months of inactivity.

Many hibernating animals become obese, insulin resistant, and start to produce high levels of insulin while they gain body fat, similar to what happens in humans with metabolic syndrome. Yet, unlike in humans, insulin resistance is reversible in hibernators.

Researchers from The University of Utah evaluated genetic factors that could be shared between humans and hibernating mammals and help explain the biological regulation of human obesity and metabolic disorders.

“Hibernators have evolved an incredible ability to control their metabolism,” Christopher Gregg, PhD, a co-author of the study, said in a university news story. “We believe that understanding the parts of the genome that are linked to hibernation will help us learn to control risks for some [of] these major diseases.”

The team started by comparing the genome of the thirteen-lined ground squirrel, little brown bat, gray mouse lemur, and lesser Madagascar hedgehog tenrec, which can be found in distant parts of the world.

Results revealed small, non-coding DNA sequences in all these animals. These sequences — named parallel accelerated regions (pARs) — could also be found within the human genome, where they were mostly located near genes linked to obesity such as the “Fat Mass and Obesity” (FTO) region. Notably, this specific DNA sequence is currently recognized as the strongest genetic risk factor for human obesity.

To further explore this potential association, the team analyzed available genetic data from people with PWS and healthy volunteers.

This revealed 456 genomic elements, including 364 that could control obesity-associated manifestations. These non-coding regulatory sequences were located near 114 obesity susceptibility genes, including 51 genes previously linked to PWS.

“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,” Elliot Ferris, the study’s lead author, said. “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.”

Based on these findings, the team believes that hibernators have evolved ways to “turn off” specific genetic elements controlling the activity of obesity-related genes compared to mammals that do not hibernate.

More detailed analyses on these newly discovered sequences may provide new knowledge on how to evaluate and control obesity risks in humans.

The team is testing the identified pARs in mice using a modified CRISPR genome editing tool.

“Our findings provide foundations to functionally dissect the noncoding regulatory mechanisms controlling obesity and hibernation,” the scientists stated.

“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,” Gregg said.

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