When Heiko Jansen joined the Washington State University (WSU) College of Veterinary Medicine, he intended to continue his work on investigating the seasonal shifts in the sheep brain that regulate their annual reproductive cycles. However, a serendipitous opportunity to examine a grizzly bear’s brain redirected his research focus. Now Jansen's team at the WSU Bear Research, Education, and Conservation Center studies bear physiology during hibernation to gain further insights into human health and disease.
By examining how grizzly bears regulate metabolism and insulin sensitivity during hibernation, Heiko Jansen and his team hope to gain a better understanding of human diseases.
Washington State University College of Veterinary Medicine
How might the study of bear physiology contribute to understanding and treating human diseases?
Grizzly bears undergo seasonal metabolic changes. Compared to the active season, bears drop their metabolic rate by approximately 75 percent during hibernation. I think analyzing how the animals facilitate these alterations could improve scientists’ comprehension of some human diseases and help uncover potential treatment options. For example, if we could find an approach that increases metabolic rate in humans, we could apply that therapy to patients with metabolic disorders, such as type 2 diabetes.
Additionally, bears accumulate a considerable amount of fat when preparing for hibernation. But the animals do not exhibit the pathological characteristics observed in humans with obesity, even though the animals become insulin resistant during hibernation.1 Unlike people with type 2 diabetes, grizzly bears can reverse this resistance in the active season. Using cell culture, we determined that adipocytes collected from hibernating bears become sensitive to insulin when cultured in bear serum obtained during the active season. This indicates that there are circulating factors that resensitize the cells to insulin. We are still tracking down at the cellular level what genes and proteins are responsible for making this transition, and we have discovered thousands of candidate genes and several potential circulating proteins.2
How do grizzly bears compare to more traditional animal models?
During hibernation, bears do not decrease their body temperature as drastically as rodent hibernators, such as marmots and ground squirrels. This is an advantage for us, as bears experience body temperatures that are more similar to those of humans. Consequently, I think bears are a more tractable model to translate our findings to humans.
Due to their large size, bears also provide us with ample blood and tissue samples. The grizzly bears at the WSU Bear Center voluntarily provide blood, and we reward them with honey as a positive reinforcement. Moreover, we acquire adipose, liver, and muscle tissue through anesthetized biopsies.
However, we only have 11 bears at the facility. As a result, we have much less flexibility in terms of experimental design compared to researchers using rats or mice. My team prides itself on constructing very carefully designed experiments to obtain statistically viable data.
How do you study bear cells during hibernation?
My team collects adipose and blood samples from the grizzly bears during the active season and hibernation.3 We then cryopreserve the preadipocytes and keep the separated serum in ultra-cold storage. When running an assay, we expand the cells and induce their differentiation into adipocytes in the presence of the serum. By freezing the cells, we do not need to perform invasive procedures on the animals continually. Additionally, this setup allows us to directly compare cells from both seasons in the same experiment, including examining differences in the adipocytes’ oxygen consumption and extracellular acidification rates or gene expression.4,5
What are your long-term goals for this research?
When we started this work 10 years ago, we thought that once we pinpointed these insulin sensitizers, we could potentially devise new therapeutic approaches to treat type 2 diabetes and obesity. Nowadays, glucagon-like peptide-1 (GLP-1) drug development has taken the forefront. However, we are still very interested in understanding the mechanisms behind the seasonal insulin sensitivity switches in bears because I think this process is different from how the existing drugs work. Physicians could then use a novel drug based on this research alone or in conjunction with GLP-1 analogs. Ultimately, there is no shortage of targets that we can uncover in this work, but it is going to take time to develop a therapy.
Despite the reduction in metabolic rate, we also observed that hibernating grizzly bears exhibit active circadian rhythms.5 This was surprising because they are energetically expensive to produce. As a result, circadian rhythms must be important to the animal’s physiology, and we plan to continue exploring how these cycles relate to their metabolism.
This interview has been condensed and edited for clarity.
- Rigano KS, et al. Life in the fat lane: Seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears. J Comp Physiol B. 2017;187(4):649-676.
- Saxton MW, et al. Serum plays an important role in reprogramming the seasonal transcriptional profile of brown bear adipocytes. iScience. 2022;25(10):105084.
- Gehring JL, et al. A protocol for the isolation and cultivation of brown bear (Ursus arctos) adipocytes. Cytotechnology. 2016;68(5):2177-2191.
- Hogan HRH, et al. Changing lanes: Seasonal differences in cellular metabolism of adipocytes in grizzly bears (Ursus arctos horribilis). J Comp Physiol B. 2022;192(2):397-410.
- Vincent EP, et al. Circadian gene transcription plays a role in cellular metabolism in hibernating brown bears, Ursus arctos. J Comp Physiol B. 2023;193(6):699-713.
