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Osteocalcin, Not Adrenaline, Drives Fight Or Flight Response

alex mas

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article of september 2019:
Bone, not adrenaline, drives fight or flight response

When faced with a predator or sudden danger, the heart rate goes up, breathing becomes more rapid, and fuel in the form of glucose is pumped throughout the body to prepare an animal to fight or flee.

These physiological changes, which constitute the "fight or flight" response, are thought to be triggered in part by the hormone adrenaline.

But a new study from Columbia researchers suggests that bony vertebrates can't muster this response to danger without the skeleton. The researchers found in mice and humans that almost immediately after the brain recognizes danger, it instructs the skeleton to flood the bloodstream with the bone-derived hormone osteocalcin, which is needed to turn on the fight or flight response.

"In bony vertebrates, the acute stress response is not possible without osteocalcin," says the study's senior investigator Gérard Karsenty, MD, PhD, chair of the Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons.

"It completely changes how we think about how acute stress responses occur."

Why Bone?

"The view of bones as merely an assembly of calcified tubes is deeply entrenched in our biomedical culture," Karsenty says. But about a decade ago, his lab hypothesized and demonstrated that the skeleton has hidden influences on other organs.

The research revealed that the skeleton releases osteocalcin, which travels through the bloodstream to affect the functions of the biology of the pancreas, the brain, muscles, and other organs.

A series of studies since then have shown that osteocalcin helps regulate metabolism by increasing the ability of cells to take in glucose, improves memory, and helps animals run faster with greater endurance.

Why does bone have all these seemingly unrelated effects on other organs?

"If you think of bone as something that evolved to protect the organism from danger -- the skull protects the brain from trauma, the skeleton allows vertebrates to escape predators, and even the bones in the ear alert us to approaching danger -- the hormonal functions of osteocalcin begin to make sense," Karsenty says. If bone evolved as a means to escape danger, Karsenty hypothesized that the skeleton should also be involved in the acute stress response, which is activated in the presence of danger.

Osteocalcin Necessary to React to Danger

If osteocalcin helps bring about the acute stress response, it must work fast, in the first few minutes after danger is detected.

In the new study, the researchers presented mice with predator urine and other stressors and looked for changes in the bloodstream. Within 2 to 3 minutes, they saw osteocalcin levels spike.

Similarly in people, the researchers found that osteocalcin also surges in people when they are subjected to the stress of public speaking or cross-examination.

When osteocalcin levels increased, heart rate, body temperature, and blood glucose levels in the mice also rose as the fight or flight response kicked in.

In contrast, mice that had been genetically engineered so that they were unable to make osteocalcin or its receptor were totally indifferent to the stressor. "Without osteocalcin, they didn't react strongly to the perceived danger," Karsenty says. "In the wild, they'd have a short day."

As a final test, the researchers were able to bring on an acute stress response in unstressed mice simply by injecting large amounts of osteocalcin.

Adrenaline Not Necessary for Fight or Flight

The findings may also explain why animals without adrenal glands and adrenal-insufficient patients -- with no means of producing adrenaline or other adrenal hormones -- can develop an acute stress response.

Among mice, this capability disappeared when the mice were unable to produce large amounts of osteocalcin.

"This shows us that circulating levels of osteocalcin are enough to drive the acute stress response," says Karsenty.

Physiology the New Frontier of Biology

Physiology may sound like old-fashioned biology, but new genetic techniques developed in the last 15 years have established it as a new frontier in science.

The ability to inactivate single genes in specific cells inside an animal, and at specific times, has led to the identification of many new inter-organ relationships. The skeleton is just one example; the heart and muscles are also exerting influence over other organs.

"I have no doubt that there are many more new inter-organ signals to be discovered," Karsenty says, "and these interactions may be as important as the ones discovered in the early part of the 20th century."
 

Nokoni

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Messages
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article of september 2019:
Bone, not adrenaline, drives fight or flight response

When faced with a predator or sudden danger, the heart rate goes up, breathing becomes more rapid, and fuel in the form of glucose is pumped throughout the body to prepare an animal to fight or flee.

These physiological changes, which constitute the "fight or flight" response, are thought to be triggered in part by the hormone adrenaline.

But a new study from Columbia researchers suggests that bony vertebrates can't muster this response to danger without the skeleton. The researchers found in mice and humans that almost immediately after the brain recognizes danger, it instructs the skeleton to flood the bloodstream with the bone-derived hormone osteocalcin, which is needed to turn on the fight or flight response.

"In bony vertebrates, the acute stress response is not possible without osteocalcin," says the study's senior investigator Gérard Karsenty, MD, PhD, chair of the Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons.

"It completely changes how we think about how acute stress responses occur."

Why Bone?

"The view of bones as merely an assembly of calcified tubes is deeply entrenched in our biomedical culture," Karsenty says. But about a decade ago, his lab hypothesized and demonstrated that the skeleton has hidden influences on other organs.

The research revealed that the skeleton releases osteocalcin, which travels through the bloodstream to affect the functions of the biology of the pancreas, the brain, muscles, and other organs.

A series of studies since then have shown that osteocalcin helps regulate metabolism by increasing the ability of cells to take in glucose, improves memory, and helps animals run faster with greater endurance.

Why does bone have all these seemingly unrelated effects on other organs?

"If you think of bone as something that evolved to protect the organism from danger -- the skull protects the brain from trauma, the skeleton allows vertebrates to escape predators, and even the bones in the ear alert us to approaching danger -- the hormonal functions of osteocalcin begin to make sense," Karsenty says. If bone evolved as a means to escape danger, Karsenty hypothesized that the skeleton should also be involved in the acute stress response, which is activated in the presence of danger.

Osteocalcin Necessary to React to Danger

If osteocalcin helps bring about the acute stress response, it must work fast, in the first few minutes after danger is detected.

In the new study, the researchers presented mice with predator urine and other stressors and looked for changes in the bloodstream. Within 2 to 3 minutes, they saw osteocalcin levels spike.

Similarly in people, the researchers found that osteocalcin also surges in people when they are subjected to the stress of public speaking or cross-examination.

When osteocalcin levels increased, heart rate, body temperature, and blood glucose levels in the mice also rose as the fight or flight response kicked in.

In contrast, mice that had been genetically engineered so that they were unable to make osteocalcin or its receptor were totally indifferent to the stressor. "Without osteocalcin, they didn't react strongly to the perceived danger," Karsenty says. "In the wild, they'd have a short day."

As a final test, the researchers were able to bring on an acute stress response in unstressed mice simply by injecting large amounts of osteocalcin.

Adrenaline Not Necessary for Fight or Flight

The findings may also explain why animals without adrenal glands and adrenal-insufficient patients -- with no means of producing adrenaline or other adrenal hormones -- can develop an acute stress response.

Among mice, this capability disappeared when the mice were unable to produce large amounts of osteocalcin.

"This shows us that circulating levels of osteocalcin are enough to drive the acute stress response," says Karsenty.

Physiology the New Frontier of Biology

Physiology may sound like old-fashioned biology, but new genetic techniques developed in the last 15 years have established it as a new frontier in science.

The ability to inactivate single genes in specific cells inside an animal, and at specific times, has led to the identification of many new inter-organ relationships. The skeleton is just one example; the heart and muscles are also exerting influence over other organs.

"I have no doubt that there are many more new inter-organ signals to be discovered," Karsenty says, "and these interactions may be as important as the ones discovered in the early part of the 20th century."
Nice find. Very interesting and, to me, completely amazing. The full study is here: https://www.sciencedirect.com/science/article/pii/S1550413119304413?via=ihub

"The sympathetic nervous system that releases catecholamine into peripheral organs is considered to be the ultimate mediator of the ASR in vertebrates (Axelrod and Reisine, 1984, Ulrich-Lai and Herman, 2009). In addition, circulating glucocorticoid hormones surge during an ASR, suggesting that an endocrine mediation of the ASR may exist. As steroids, glucocorticoid hormones act mainly, albeit not only, at the transcriptional level and need hours to regulate physiological processes (Tsai and O'Malley, 1994), something that seems inconsistent with the need for an immediate response. Although this certainly does not rule out that glucocorticoid hormones may be implicated in some capacity in the ASR, it suggests the possibility that other hormones, possibly peptide ones, could mediate the ASR. This is why, in considering that an original purpose of bone was to escape danger, we asked whether bone-derived hormones contribute to the ASR in bony vertebrates."

So adrenaline would just take too long. They found evidence that glutamate activates the osteoblasts in bone to release osteocalcin, which then turns down parasympathetic tone, leaving sympathetic tone unopposed. The full ASR results, even in animals with no adrenal glands at all. Like I said, amazing.
 

Peater

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Really interesting. What's the view on this hormone in context of Peat - is it controllable? Would it be considered outside of the HPA axis?
 

Nokoni

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Really interesting. What's the view on this hormone in context of Peat - is it controllable? Would it be considered outside of the HPA axis?
I had the same question. Don't know what Peat would say but I did a quick search on "lithium glutamate" and discovered that lithium downregulates glutamate (and unfortunately dopamine) and upregulates GABA. So taking lithium might dampen the Acute Stress Response, which would probably make it Peat-ish. I've been experimenting with lithium orotate and the effect is remarkable. All of this may explain why.
 

Peater

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I had the same question. Don't know what Peat would say but I did a quick search on "lithium glutamate" and discovered that lithium downregulates glutamate (and unfortunately dopamine) and upregulates GABA. So taking lithium might dampen the Acute Stress Response, which would probably make it Peat-ish. I've been experimenting with lithium orotate and the effect is remarkable. All of this may explain why.

Thank you, do you stick to the standard 5mg dose? And at what time of day?
 

Nokoni

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It's only been a week or two so I'm still working on dosing. Yesterday I took 4 of them, morning, midday, and 2 at night, and that seemed to work out well. In this video, , someone who goes by "NootropicsExpert" advocates as much as 2 several times per day. (If you watch the vid, notice that he seems to have a dry mouth. Lithium, which is just above sodium on the periodic table, makes you thirsty. Kinda like eating potato chips :):.)
 

LeeLemonoil

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Probably one of the factors why competitive sports are so popular and recreational. It‘s not threatening so parts of the more devastating mental threat and stress - system doesn’t factors in.
But the more physical, osteo-muscular mechanisms do and this might help with beneficial osteocalcin spikes which has been shown to be pro-androgenic among other beneficial things
 

Nokoni

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So Osteocalcin could be considered „good stress“?
No I don't think it's good for you at all unless you're being chased by a bear :):.
 

Nokoni

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Probably one of the factors why competitive sports are so popular and recreational. It‘s not threatening so parts of the more devastating mental threat and stress - system doesn’t factors in.
But the more physical, osteo-muscular mechanisms do and this might help with beneficial osteocalcin spikes which has been shown to be pro-androgenic among other beneficial things
Right, the study above made the following point: "Osteocalcin enhances multiple physiological processes in peripheral organs and the brain," and it talks about it some.
 

Nokoni

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ScurveDream

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Adrenaline is now bonealin?

Bonadrenaline?

This is definitely a different approach I would've never guessed on how the flight or fight system works.

With this in mind it might call for different ways of looking at anxiety/nervousness, maybe?

The major factors I thought that played in to anxiety issues would be GABA and the amygdala, among several other neurochemical pathways/etc.
 

BigChad

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No I don't think it's good for you at all unless you're being chased by a bear :):.

Doesnt vitamin k raise osteocalcin? Does this mean mk4 should be limited.

I had the same question. Don't know what Peat would say but I did a quick search on "lithium glutamate" and discovered that lithium downregulates glutamate (and unfortunately dopamine) and upregulates GABA. So taking lithium might dampen the Acute Stress Response, which would probably make it Peat-ish. I've been experimenting with lithium orotate and the effect is remarkable. All of this may explain why.

Isnt lithium goitrogenic and lowers thyroid hormones? Has peat ever spoken favorably about it? Id imagine he would be against it. Its not an essential nutrient right
 

Nokoni

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Doesnt vitamin k raise osteocalcin? Does this mean mk4 should be limited.
Don't know if it does but everything does good and bad. The keepers are the ones where good clearly outweighs bad, and vitamin K would almost certainly be a keeper.

Isnt lithium goitrogenic and lowers thyroid hormones? Has peat ever spoken favorably about it? Id imagine he would be against it. Its not an essential nutrient right
I have read that it can lower thyroid but I think that mostly relates to the huge doses used by doctors. Besides I supplement thyroid so if I need more I'll take more.

In "Thyroid, insomnia, and the insanities" Ray has said the following about lithium:

"In the peiodic table of the elements, lithium is immediately above sodium, meaning that it has the chemical properties of sodium, but with a smaller atomic radius, which makes its electrical charge more intense. Its physiological effects are so close to sodium’s that we can get clues to sodium’s actions by watching what lithium does.

"Chronic consumption of lithium blocks the release of adrenalin from the adrenal glands, and it also has extensive antiserotonin effects, inhibiting its release from some sites, and blocking its actions at others.

"Lithium forms a complex with the ammonia molecule, and since the ammonia molecule mimics the effects of serotonin, especially in fatigue, this could be involved in lithium’s antiserotonergic effects. Ammonia, like serotonin, impairs mitochondrial energy production (at a minimum, it uses energy in being converted to urea), so anti-ammonia, anti-serotonin agents make more energy available for adaptation. Lithium has been demonstrated to restore the energy metabolism of mitochondria (Gulidova, 1977).

"Therapies that have been successful in treating “schizophrenia” include penicillin, sleep therapy, hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin, histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and increased carbon dioxide acidifies cells, preventing serotonin secretion."

So "lithium makes fundamental contributions to the restoration of biological energy" seems like something of an endorsement.
 
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