SMRT Grant Winner: Uncovering the Metabolic Secrets of Hibernation

What has four legs, lots of fat and fur, and will possibly help uncover novel mechanisms to combat diabetes?

Grizzly bears!
If humans were to undergo regular, extended cycles of weight gain and inactivity, they’d likely end up with obesity, muscle atrophy, or type 2 diabetes. But grizzly bears experience no ill effects from their annual fat gain and sedentary hibernation. Somehow they are able to switch their insulin resistance between seasons, and researchers at Washington State University are hoping to figure out how, with possible therapeutic value for humans.
We’re proud to support this outstanding research, by awarding graduate student Shawn Trojahn and Associate Professor Joanna Kelley the 2018 Plant and Animal SMRT Grant. We recently caught up with them to learn more about their research project and the bears that make it possible.
 
Why grizzly bears?
Well, we have access to an incredibly unique resource, the WSU Bear Research, Education, and Conservation Center, the only dedicated research populations of grizzly bears. When our lab first came to WSU five years ago, we became interested in the studies being done there, in fields from nutrition to physiology.

Scientists are really starting to appreciate hibernators.
They do some pretty unusual things and they do them well.
We could learn a lot from them.

A lot of the phenotypes that we see in hibernating bears could give us insight into genetic mechanisms that might be relevant for human diseases too. They gain and lose a lot of fat. They have insulin insensitivity during hibernation—which is what happens in type 2 diabetes— but they reverse the insensitivity in the active season.
We hypothesize that these reversible states are achieved in grizzly bears through differential expression of transcript isoforms, possibly with human homologs. Preliminary evidence from proteomic work on hibernating and non-hibernating bear serum supports this hypothesis, as there is no change in the identity of proteins present, but peptides differ between seasons.
 
What does the project entail?

We plan to compare full-length isoforms between hibernating and active bears in three metabolically active tissues: skeletal muscle, liver, and adipose.
We will also collect blood samples at different stages along the annual cycle, from six bears who have been trained from birth to take part in approved research.
The bears are pretty amazing. They can respond to cues, and present their paws for inspection, making it easy to take blood draws without the need for sedation.
 
How will  PacBio Sequencing support this project?
SMRT Sequencing with Iso-Seq analysis is perfect for this work, as it will allow us to identify the full-length isoforms that are differentially expressed between seasons.
We’ve used SMRT Sequencing for genome assembly of organisms in extreme environments, such as polar fishes, and we’ve been following the development of the Iso-Seq method since its introduction to the field. We’re extremely excited to finally have the opportunity to try it.  
 
What do you expect to find?
No one has done this before, so we have no idea what we will find. But we’re going to extract as much information as possible about alternative splicing, binding sites, regulators and protein translation. And we’re really excited to see what other questions might arise as a result. This will open up so many opportunities—the sky’s the limit.
 
UPDATE (August 2019)
We recently joined the WSU researchers as they collected samples for the project from bears at the WSU Bear Center. Read our full account of the experience on Medium, and meet the team — and Willow the bear — in the video below.
 

 
 
 
We are so excited to support this research and look forward to seeing the results. Check out our website for more information on upcoming SMRT Grant Programs.
Thank you to our co-sponsor, the University of Delaware Sequencing & Genotyping Center, for supporting the 2018 Plant and Animal Science SMRT Grant Program.