Have you been voting in Fat Bear Week? If not, today is the final day: the run-off between two heavyweights that will determine the Fattest Bear.
You probably realize that the bears get so fat in the fall because they are about to go into five months of hibernation, and need to stock up on food to sustain their metabolism as they go into winter. The Washington Post article shown below describes the remarkable phenomenon of hibernation, the potential bodily problems it poses, and new biochemical discoveries that help the bears obviate these issues and could also help immobile humans with the issue of atrophied muscles. Click to read:
Quotes from the article are indented:
But for many scientists, the true fascination of Fat Bear Week involves what happens next, when the now beachball-shaped bruins, carrying about 40 percent body fat, lumber into their dens and start hibernating. During hibernation, they remain healthy under conditions that would weaken and sicken mere humans. The bears emerge months later, lean, strong and barely affected by their months of starvation and inactivity.
Until recently, researchers could not explain how. But several fascinating new molecular studies suggest hibernation remodels bear metabolisms and gene activity in unique and dramatic ways that could have relevance for people. The fat bears can advance our understanding of diabetes, muscle atrophy, inactivity and the ingenuity of evolution.
Superficially, hibernating bears seem passive and inert. For five months or more, they do not eat, drink, urinate, defecate or move, except occasionally to turn over or shiver. Their metabolisms drop by about 75 percent. Hearts beat and lungs inflate only a few times a minute. Kidneys shut down. The bears grow profoundly insulin resistant.
If this were us, we would shed much of our muscle mass because of inactivity and probably develop diabetes, heart disease, kidney failure, frailty and other ills.
But the bears maintain their muscle and rapidly reestablish normal, healthy insulin sensitivity and organ function after hibernation.
Insulin functions to allow cells to absorb glucose from the blood to use as energy, or to convert some glucose to fat. It also helps break down fats and proteins. Normally, the onset of insulin resistance would, as the article implies, lead to diabetes and its attendant problems, but the bears are somehow able to tolerate that—as well as the muscle atrophy attendant on not moving for five months. (Muscle atrophy is a problem for people who are either paralyzed or bedridden for long periods of time.)
How do the bears do this? That’s the point of the article, which links to three scientific articles (one given below) explaining how the bears survive hibernation.
The information on fat usage came from blood samples drawn from hibernating and non-hibernating bears at Washington State University (WSU), bears trained to allow a blood draw without being anesthetized. (I guess the WSU bears also go into hibernation.)
It turns out that there is differential activation of genes in the bears during hibernation that protect them from deleterious effects of hibernation. Here are two papers cited:
By comparing the samples, [reserachers] concluded hibernation is biologically uncanny but hardly quiet. In a 2019 study, the WSU scientists and others found more than 10,000 genes in bears that work differently during hibernation vs. in autumn or spring. Many involve insulin activity and energy expenditure and most occur in the animals’ fat, which becomes quite insulin resistant during hibernation and robustly insulin sensitive immediately afterward.
Digging deeper into that process for a new study, published in September in iScience, they bathed fat cells drawn from hibernating and active bears with blood serum taken during the opposing time and watched the fat switch seasons. Fat from hibernating bears became insulin sensitive and genetically similar to fat from the active season and vice versa.
In other words, something in the blood serum of non-hibernating bears restored the insulin sensitivity of hibernating bears, and vice versa. This shows that it is something in the serum, and not in the fat, that changes during hibernation. The article continues:
Perhaps most compelling, they also identified and cross-matched hundreds of proteins in the animals’ blood and found eight that differed substantially in abundance from one season to the next. These eight proteins seemed to be driving most of the genetic and metabolic changes in the fat.
Of course correlation is not causation, and I doubt that 10,000 genes are involved in actually producing hibernation or mitigating its effects. (After all, humans have only about 25,000 protein-coding genes—more if you include as “genes” bits of DNA that do something but don’t produce proteins—and bears can’t differ that much from us. There may be changes in that many genes, but many of these may simply be side effects of natural selection changes the expression of many fewer genes.
But it’s clear that genes involved in insulin usage and sensitivity work differently in hibernating versus nonhibernating bears. What are the cues that turn these genes on and off? I doubt that we know, and the paper doesn’t say, but a good guess is that this has to do with environmental factors indicating the impending arrival of spring or fall: cues based on day length or temperature.
But what about the bears’ muscles? Why don’t they atrophy? Again, it’s due (as it must be) to differential activation of genes. And again, the gene products responsible seem to be circulated in the blood serum.
The paper below from PLoS ONE (click on screenshot to read; pdf here and reference at bottom), implicates both the blood serum and the genes involved in maintaining muscle.
The Japanese researchers bathed cultured human skeletal muscle cells in serum from either hibernating or non-hibernating black bears. What they found was significantly less degradation of protein when hibernating-bear serum was used. This appeared to be based on a gene-induced decrease in levels of two proteins and an increase in the level of another, which act in concert to preserve protein levels in the cultured cells. (The protein made in reduced amount breaks down muscle while the others promote and sustain muscle growth.) Altogether, changes in gene action appears to keep the bears’ muscles fairly intact as they go through hibernation.
Now these are cultured human cells, not bear cells, and the experiment was done in vitro rather than in vivo, but it gives a very promising lead to how bears keep their muscles strong during hibernation.
The Post article also lays out the potential uses of this information in human health.
Fat.
Potentially, these same eight proteins, which also appear in human blood, might at some point be harnessed pharmaceutically to improve insulin sensitivity or treat diabetes and other metabolic disorders in people, Kelley said. But that possibility lies far in the future and requires vastly more research with bears and us (although perhaps not in close proximity).
Muscle.
The ultimate aim of this research, [author] Miyazaki said, is to isolate and refine all of the substances and processes in hibernating bears’ blood and elsewhere in their bodies that protect them from muscle wasting, with the hope that these same elements might treat atrophy from bed rest or aging in people.
“There is probably no better way to maintain a healthy lifestyle than through physical exercise,” he said, but for people who cannot be active, for whatever reason, the internal operations of slumbering bears might someday provide respite from frailty.
It’s important to remember that these remarkable changes are certainly due to evolution via natural selection, as it’s hard to imagine a random process like genetic drift causing evolutionary changes that are certainly adaptive.
As Ernst Mayr emphasized, many important evolutionary changes in animals begin with a change in behavior. Perhaps bears in cold areas survived better if they underwent a period of low activity during winter when food is scarce (this behavioral change could reflect genetic variation), and then those quiescent bears who also had mutations affecting fat and muscle metabolism would be those most likely to survive hibernation, leaving their genes to future bear generations.
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Miyazaki M, Shimozuru M, Tsubota T. (2022) Supplementing cultured human myotubes with hibernating bear serum results in increased protein content by modulating Akt/FOXO3a signaling. PLoS ONE 17(1): e0263085. https://doi.org/10.1371/journal.pone.0263085
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Amazing stuff! The genius of natural selection in action. (I mean ”genius” non-teleologically, of course.)
On a more selfish note. I’m glad that the bears are about to hibernate. They are remarkably common in our residential area, as evidenced by the almost daily online reports(with video!) from neighbors with Ring doorbells. Once they are safely rendered glucose-intolerant and inert, my wife and I will be able to go out hiking again.
But what are the intercellular signalling mechanisms? In other words, Quis custodiet ipsos custodes?
It appears to be that the gene products specified, at least in the “muscle example” are circulated in the blood to the cells, and those products activate the needed genes. Now we may not know how they do that (gene regulation in development is still largely a mystery), but the “mechanisms” presumably involve the gene products identified.
That is highly interesting. One could wonder if there are applications in long-term space travel, for example.
What a fascinating thought! In-flight hibernation has long been a staple of science fiction space travel (until warp drive was invented). In the future, I guess hibernation is more likely than warp drive.
I’m trying to think of the new Ursine Starfleet Academy program – to boldly hibernate where no bear has … hibernated… before….
First episode : The Salmon Trap
I remember reading that 3 days of starvation would reset insulin production in humans, reversing diabetes. I was unable to find any reputable studies to confirm this. The only study I did find said that fasting first reduces fat in the body before starting on muscle mass. This sounds like a call for studies of fasting to be made before the woo brigade start adding their contribution.
Thanks for sharing this Jerry. Fascinating as always.