In Rats And Traumatized Children, 'Hunger Hormone' Appears Key In Ill Effects Of Stress

If you've ever heard of ghrelin, it was probably in connection with the quest for better weight-loss drugs; ghrelin is normally thought of as a hormone that regulates feelings of hunger.

But new research out of Massachusetts General Hospital nails down a link between ghrelin and the health effects of traumatic stress. Led by Ki Goosens, an assistant professor of neurology and investigator in the MassGeneral Institute for Neurodegenerative Disease, the team found that among children in a violent, Taliban-affected area of Pakistan, those who'd been traumatized had higher ghrelin levels — and they stayed higher for years.

"Children who had lost a loved one or been injured in a terror attack had roughly twice the baseline level of circulating ghrelin, and that's remarkably similar to what we see in our rodent studies," Goosens says.

Her next goal is to figure out how to reverse the effects of ghrelin, in hopes of preventing or treating post-traumatic stress disorder and other ill effects of trauma. In rats, blocking ghrelin during and after trauma did help, she found, but there are currently no federally approved ghrelin-blockers for humans. Our edited exchange:

How would you sum up what you found?

Our most important finding is that both adolescent rodents and adolescent humans who are exposed to trauma have elevated levels of the hormone acyl-ghrelin in their blood for very long periods of time after stress ends. In rodents, that's months, and in humans, that's years.

What did you do in this study to find that?

We worked with a team of investigators in Pakistan, and they recruited children from a Taliban-affected area in Pakistan that has a lot of terrorist activity, so there are a lot of traumatized children and adults in that area. They recruited children who had either been injured or lost loved ones in a terror attack, or who had never been injured or lost loved ones in a terror attack. And they collected blood samples, which we analyzed for this hormone. They also collected a lot of other data on these children about their health status and other things.

What we were looking for was: In otherwise healthy children who had been exposed to trauma one or more years ago, how did their ghrelin levels compare to children who had never been exposed to this kind of trauma or stress? And again, what we found was that the children who had lost a loved one or been injured in a terror attack had roughly twice the baseline level of circulating ghrelin. And that's remarkably similar to what we see in our rodent studies.

This was on average about four and a half years after the terror attack for these children. So to have a hormone be doubled, four and a half years later, is an extremely long time for such a change to persist.

What are the implications for humans?

The reason we're interested in this question is because stress in adolescence is known to have a huge impact on health outcomes later in life. There can even be decades that pass between when you experience the stress as an adolescent and when you later see negative health outcomes.

One thing that happens is that if you've experienced adolescent stress and you encounter trauma in adulthood, you're more likely to develop PTSD from it. And so it's very clear that the stress in adolescence is having some kind of very long-term change that persists for years, if not decades, into adulthood, to convey this kind of risk.

So in my lab, we're very interested in: What are the things that stress does to the body that can lead to these negative health outcomes so much later in life?

Did you only look at ghrelin? What about more typical stress hormones, like cortisol?

In this particular study we only looked at ghrelin but that's not because we think ghrelin is the only stress hormone. There have been other studies that have tried to look at more canonical, classical stress hormones, like cortisol, and long term effects of cortisol, and there just aren't huge changes that persist. There there may be persistent dysregulation but it's more subtle.

My lab focuses on ghrelin not because we think it's the only hormone involved but because we think it's another hormone that's an important and yet largely unrecognized player. And for us, it was really important to see if, in fact, ghrelin was elevated by stress in humans. We and others have seen it in so many other animal species. But this is the first study to look at humans and show that it generalizes to people as well.

So could it possibly have implications for prevention or treatment?

That's what we're hoping. We did a second study using a rat model of PTSD, where if we chronically stress rats in adolescence and then they encounter a trauma called fear conditioning in adulthood, they show something like PTSD. That is, they learn to fear excessively compared to unstressed animals. Our working hypothesis was that maybe when you're stressed in adolescence and you have this elevated level of ghrelin, maybe this is one of the things that leads to subsequent PTSD vulnerability. If that's true, then you would think that blocking the enhanced ghrelin signaling between adolescence and when you encounter trauma might prevent PTSD.

So that's what we looked at in our rodent model. During stress and after stress, we administered to these adolescent rats a ghrelin-receptor antagonist, to reduce the effects of ghrelin during that time.

What we found was that if we reduce the effects of ghrelin during chronic stress and in the period after, we would prevent the PTSD phenotype in those previously stressed rats. That is, they would learn to fear in a normal, adaptive way, as though they had never been stressed. From our perspective, that's a really great thing, that links the hormone to excessive fear learning, and suggests that if you can reduce it during and after stress, that might be a great therapeutic angle to take.

But it had to be both during and after stress?

Right. Just blocking ghrelin signaling during stress was not enough to prevent PTSD in those rats if there was a temporal gap between the end of stress exposure and the subsequent trauma. And similarly, if you wait until after they're stressed and you start blocking ghrelin receptors, we also saw there that those animals still developed PTSD. So what that suggests is that during the two weeks of stress when the ghrelin signaling is elevated, it's already causing some kind of change in the brain and perhaps also the body. Blocking the ghrelin receptors after stress is too late. You really need this sort of early intervention to stop a cascade of vulnerability.

So is there anything that blocks ghrelin in humans? 

I wish. Nothing that's FDA-approved. Though there's a lot of interest in developing drugs that can block ghrelin or methods for reducing ghrelin. A lot of it has been developed in the context of controlling appetite. But although we call ghrelin a 'hunger hormone,' that's in some ways a misnomer because it has a much broader role.

What will you look at next?

A big question for us is: If you want to translate this into a therapy, at what point can you intervene to reverse the effects of too much ghrelin, and how long do you have to intervene for?