Hibernation Provides Genetic Clues to Understanding Obesity

Hibernation Provides Genetic Clues to Understanding Obesity
Fat man holding a measurement tape

Researchers studying the genetics of hibernating mammals have found clues associated with metabolism. Hibernating mammals became obese, insulin resistant and hyperinsulinemic to store fat in preparation for long periods of uninterrupted sleep.  Yet they emerge from hibernation trim and generally healthy.

In their study researchers from the University of Utah compared the genomes of four hibernating mammals—thirteen-lined ground squirrel, little brown bat, gray mouse lemur, and lesser Madagascar hedgehog tenrec—with humans searching for genetic links modulating hibernation, obesity and metabolic disorders. They identified 364 potential genetic elements they believe could have a role in regulating hibernation and obesity.

The team discovered that these hibernating mammals had independently evolved short, non-coding DNA snippets called parallel accelerated regions (AR). “ARs are evolutionarily conserved elements with significantly increased nucleotide substitution rates in a particular lineage,” the authors said in their paper published in Cell Reports on November 26. “Hibernating ARs could reveal important cis-regulatory elements controlling obesity-related phenotypes.” In their study, they identified 456 genomic elements, including 364 cis-regulatory elements for controlling obesity phenotypes.

Parallel accelerated regions were found to be located near genes linked to obesity in humans.  Of the more than 250 known genomic loci and 123 genes known to have a role in obesity in humans, the strongest gene region in humans is known as the Fat Mass and Obesity (FTO) gene locus.

In this study, the researchers learned that the FTO locus in human contains many hibernator ARs. This discovery suggests that parts of the genome that are linked to hibernation may shed light on understanding the risks for obesity and associated disorders in humans

Genetic Enrichment found in Prader-Willi disorder

The parallel ARs were all found in regions of the 98 percent of the genome that includes non-coding elements. Similarly, variants of the FTO locus associated with obesity are noncoding. The authors conclude that “investigating noncoding cis-regulatory mechanisms can help us understand the basis of obesity.”

To solidify this link, the researchers examined genes involved in Prader-Willi Syndrome (PWS), a human genetic disorder that triggers insatiable appetite and leads to morbid obesity. They found that genes linked to PWS also have more hibernator accelerated regions compared to genes not associated with the syndrome.  Based on this and other findings, the researchers theorize that hibernators have evolved ways to “turn off” specific genetic elements controlling the activity of obesity genes compared to mammals that do not hibernate.

The researchers believe that they may have uncovered candidate master regulatory switches in the genome for controlling mammalian obesity.

Moving forward the researching will be testing these 364 cis-regulatory elements in mice with CRISPR epigenome editing technology. Their goal is to perform targeted functional studies of each of these elements to learn more about noncoding mechanisms controlling obesity, hypometabolic states, and feeding behaviors.