Shared physiology between hypothyroid humans and hibernating bears.

Bears are healthy obese and inactive animals

Bears are amazing animals. They hibernate for about six months every year. Before entering hibernation, they accumulate large amounts of fat and become highly obese in preparation for these six months without food and water.

Obesity and inactivity are two strong risk factors for developing many different diseases in humans. Despite exposure to these risk factors, diseases such as diabetes, cardiovascular diseases, bone and muscle loss, and bed sores have not been observed in bears.

The missing key to hibernation

By comparing the molecular conditions of blood and tissue samples taken during hibernation in winter with samples taken during the active summer period, our objective was to identify molecules involved in the extraordinary metabolic transformation to hibernation. The regulators preserving health in hibernating bears likely also have relevance for maintaining health in obese or inactive humans and could provide important insight toward development of new human therapies or new health protective strategies.

Thyroid hormones are major regulators of metabolism

Hibernating bears lower their metabolic rate to approximately 25% of the rate during the active state and survive merely by consumption of fat deposits stored during the hyperphagic phase at the end of summer.

Thyroid hormones are the major endocrine regulators of basal metabolic rate in humans and the purpose of our study was to determine how serum thyroid hormone levels change during hibernation as compared to the active state.

Bears have low thyroid hormone levels

We measured the levels of the two thyroid hormones – thyroxine (T4) and triiodothyronine (T3) – in active and hibernating Scandinavian brown bears. Both hormones were reduced during hibernation to less than 44% for T4 and 36% for T3 of the levels during summer.

The thyroid hormones are bound and transported by binding proteins in the plasma. Like most plasma proteins, thyroid hormone carriers are produced in the liver. We analyzed the gene expression of the major thyroid hormone carrier proteins in the liver based on a previously published dataset from Grizzly bears. We found that the major thyroid hormone carrier – thyroxine binding globulin (TBG) – was increased more than 4-fold compared to the level in the active state.

The large increase in the expression level of the carrier protein TBG in combination with the decrease in thyroid hormone levels lead to a decrease in the free, bioactive thyroid hormone levels and strongly indicate that bears have little active thyroid hormones during hibernation.

Similar symptoms of humans and bears with low thyroid hormone levels

Interestingly, humans with very low thyroid hormone levels experience symptoms very similar to the phenotype we observe in hibernating bears: Up to 50% reduction in basal metabolic rate, slower heart rate (bradycardia), lower body temperature (hypothermia), tiredness (fatigue), and defecation problems (constipation).

This observation led us to propose that decreased thyroid hormone signaling is a key regulator of hibernation physiology in bears and function to protect energy stores by reducing the metabolic rate.

Bears as translational models for human therapies

Bears can serve as a translational model for developing new strategies to maintain human health in our modern and less physically active societies. Perhaps bears can even teach us how to induce hibernation in humans.

Induction of reduced metabolism in humans could have relevance for treatment of disease-related weight loss, such as that observed in cancer patients, or during space missions, where food resources are limited.

We hope that other researchers will be inspired by our results and see the potential of using the hibernating brown bear as a source for identifying new human therapies.

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Anne Mette Frøbert, Malene Brohus, Ole Fröbert, and Michael Toft Overgaard

Anne Mette Frøbert, MSc, PhD, received her PhD degree in 2022 from the Department of Chemistry and Bioscience at Aalborg University. During her PhD studies, she investigated how bears avoid complications related to obesity and inactivity during the six-month long hibernation period. Today she works in the private sector.

Malene Brohus, MSc, PhD, is an assistant professor at the Dept. of Chemistry and Bioscience at Aalborg University, Denmark. Her research focuses mainly on the role of proteins in health and disease, with a focus on understanding the molecular mechanisms that underlie extraordinary health features, such as those seen in hibernating bears, or human disease.

Ole Fröbert, MD, PhD, is an adjunct Professor and invasive consultant cardiologist at Örebro University Hospital, Sweden and Professor at Aarhus University, Denmark. Ole has lead a number of large clinical trials in cardiology with a focus on drug repurposing while introducing new trial designs. He is coordinating a multidisciplinary translational research initiative on brown bears.

Michael Toft Overgaard, MSc, PhD, is a professor in protein science at the Dept. of Chemistry and Bioscience at Aalborg University, Denmark. His research focuses on the role of proteins in health and disease. This includes identification of endocrine factors and regulatory mechanisms that enable the hibernating brown bear physiology.

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• Low thyroid hormone levels may adapt brown bears to hibernation - 17th May 2023