Its bone hormone osteocalcin and not adrenalin that causes "fight or flight" response finds Study

It is not adrenaline but bone-derived hormone osteocalcin causes "fight or flight" response finds a new study.

"Fight or flight" response till now was thought to be triggered in part by the hormone adrenaline. The response occurs when faced with sudden danger, that causes the heart rate to increase, breathing to become more rapid and fuel in the form of glucose is pumped throughout the body to prepare the body to fight or fee. Now, a recent study published in the journal Cell Metabolism suggests that it is the bone-derived hormone osteocalcin that is needed to turn on the fight or flight response.

The Columbian researchers found that the bony vertebrates can't muster this response to danger without the skeleton. In mice and humans 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.

Gérard Karsenty, chair of the Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons, and colleagues hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, they showed here that a bone-derived signal is necessary to develop an acute stress response (ASR).

"In bony vertebrates, the acute stress response is not possible without osteocalcin," said Dr. Karsenty. "It completely changes how we think about how acute stress responses occur."

"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 the 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 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."

Source: Cell Metabolism

Key takeaways from the study:

• The ASR stimulates osteocalcin release from bone within minutes.


• Glutamate uptake into osteoblasts is required for osteocalcin release during an ASR.


• Osteocalcin inhibits the parasympathetic tone during an ASR.


• In adrenal insufficiency, increased osteocalcin levels enable an ASR to occur.

To read the study in detail log on to http://dx.doi.org/10.1016/j.cmet.2019.08.012