Huh? Hunger Hormone May Be Key To Stress Effects On Mental Health

Dr. Ki Goosense and .....

Dr. Ki Goosens and Technical Associate Junmei Yao examine a piece of human brain at the McGovern Institute for Brain Research. They are looking for stress-sensitive genes that are abnormally activated in the amygdala — a brain region that regulates emotion — in people who committed suicide. (Courtesy Justin Knight Photography and McGovern Institute)

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Neuroscientist Ki Goosens does her research with black and white rats, but what she has discovered could be very relevant to humans — including her own family.

In the last eight years, three family members have become suicidal in the wake of a “major life stressor” like divorce.

“For years, they were fine, and then it triggers some cascade of vulnerability,” she said. “So I feel a sense of urgency in trying to come up with new ways to think about how we can block the ability of stress to worsen mental illness, to trigger mental illness.”

Goosens and her team at MIT’s McGovern Institute for Brain Research have just published what could be a major lead: A hormone called ghrelin — known as the hunger hormone and made in the stomach — may be a key to post-traumatic stress disorder and other stress-related mental illnesses.

The research is still early, but it raises the possibility that drugs that block ghrelin could be used to block some of the mental harm done by chronic stress.

‘I’m a neuroscientist. I study the brain. But you sort of go where the data take you.’

Goosens and her collaborators at Mass. General Hospital are now planning two studies on ghrelin in humans: One will determine whether ghrelin levels are elevated in people with anxiety disorders; the other will block ghrelin signaling in hopes of preventing stress-related relapses of depression.

Goosens never expected to be using a hunger hormone to understand stress: “If you had asked me five years ago if I would be doing something related to the stomach, I would’ve said, ‘No way, you’re crazy. I’m a neuroscientist! I study the brain,’” she said. “But you sort of go where the data take you.”

She originally set out to explore how stress affects the activity of genes in the amygdala, a part of the brain that processes emotions.

She found that when chronic stress was high, so were ghrelin levels. And unlike the hormones we usually think of as stress-related, like adrenaline, which peak and then drop quickly, the ghrelin would go up and stay up for weeks or months.

For decades, scientists have naturally expected stress hormones to be the source of stress-related mental illnesses, like PTSD. But a stomach hormone? Why would a hunger hormone be a key player in stress and fear?

Goosens obligingly speculated: “I’ve thought a lot about this,” she said. “In some ways, you can think of all organisms as just complicated food tubes, right? Most of our body is in fact a digestive tract, and our brain controls our access to food. I think probably the most primordial type of stress, that applies to humans but also to single-celled organisms, is starvation, where you don’t have enough food. And it’s when you’re starving, when your stomach is empty, that your body will produce ghrelin.

“And so what I’m thinking is that perhaps ghrelin represented a very primordial type of stress, starvation, and that over time, our brains have co-opted that signal, and use it to indicate more than just starvation — that it’s a broader indicator of other types of stress.”

Goosens began testing her ghrelin hypothesis in her lab’s rats. She kept some happy, “control” rats, unbothered in their little plastic boxes, and then there were the chronically stressed rats: For a couple of hours every day, they would be brought down to the lab and put into clear plastic bags that limited their movement — the equivalent of a straitjacket for a rat.

They were not in pain; they just couldn’t move. But they hated it. It cast them into a state of psychological stress.

After the rats had been stressed for a week or more, they and the happy control rats were taught to fear a tone: Every time they heard it, they got a tiny foot shock. Soon, just hearing the tone was enough to make the rats freeze in fear.

How long they froze showed how strong their fear was — and the rats who were chronically stressed tended to freeze at the sound of the tone for a much longer time than the unstressed rats. So they were reacting to a perceived threat something like humans with PTSD.

‘It’s really exciting to think about all these drugs that might be, in fact, re-purposed to target PTSD.’

Next, Goosens and her student Retsina Meyer — now a new-minted MIT PhD — injected the unstressed rats repeatedly with a ghrelin activator. That made the unstressed rats freeze in reaction to the tone longer, just like the stressed rats.

Then, Goosens and her team tried the opposite experiment: They took the chronically stressed rats and blocked their ghrelin receptors. Now, “when you expose them to the fear conditioning, they don’t have the enhanced fear,” she said. “They behave as though they were unstressed animals.”

Goosens has even tried removing rats‘ adrenal glands — the source of stress hormones like adrenaline and cortisol — and found that chronic stress still raises ghrelin levels and enhances the rats’ fear response. So ghrelin seems to be a truly novel pathway, independent of those classic stress hormones.

She and her team published their findings last week.

Dr. Bruce McEwen of Rockefeller University, a leading researcher on the effects of stress on the brain, says the ghrelin paper is credible work that “extends our knowledge of molecular players in fear that is certainly relevant to PTSD.”

It “opens an avenue that’s well worth studying,” he said.

After ghrelin was discovered in the 1990s, some researchers figured that if ghrelin makes you hungry, then maybe drugs to block it could help people lose weight. The drugs they developed were mostly safe — the only problem was, they didn’t work for weight loss.

Ki Goosens is hoping that now, those ghrelin-blocking drugs will find a new use: “It’s really exciting to think about all these drugs that might be, in fact, repurposed to target PTSD or other stress-sensitive mental disorders,” she said.

She knows, from her own family’s experience, how great the need is for better psychiatric drugs. She has seen her brother continue to struggle after his divorce brought on a breakdown.

“I know that stress was a major factor in his illness, and so that changed the way I thought about my own research,” she said. “Instead of just doing research to publish exciting papers and add knowledge to textbooks, as admirable as I think that is, I just decided that I really wanted to do research that would have a tangible impact in people’s lives.”

Further reading: McGovern neuroscientists discover new role for ‘hunger hormone’

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  • Ashley

    Other than the stomach hormone, are there any other known hormones that contribute to PTSD? It seems very strange to me that a stomach hormone can cause stress, and I am also confused at how this can help one lose weight but cause one to want to eat more as well. If the stomach hormone level increases in the body, wouldn’t the person become more hungry and want to eat?

  • RM

    Thank you for the press, WBUR!

    If you or your readers would like to know more, the primary
    article is open access and can be found here: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2013135a.html

    Retsina Meyer, PhD
    Neuroscience | MIT ’13

  • Susan Pease Banitt

    So, perhaps people who “overeat” because of severe stress are merely attempting to lower ghrelin levels and this behavior is perfectly normal.

    • RM

      Exactly! Stress raises ghrelin levels. Ghrelin increases motivation for “comfort foods”. And, for some people, stress causes increased desire for those same comfort foods!

      Although there is a population of people who, when stressed, do not eat.

      • betts

        Of those people who suffer with PTSD, do they more often loss appetite when anxious?

        • RM

          I do not have specific data on the number of patients who exhibit stress-induced appetite loss but there are a great number of PTSD patients with metabolic syndrome or comorbid obesity. Additionally, my second paper (not published yet) demonstrates that short-term and long-term stress can have very different effects. Therefore, a patient could be both: a stress non-eater for short-term periods but become a stress eater in the long run.

  • CRH

    Could they study people who have undergone gastric bypass? I think the stomach stops producing grehlin (not sure though). Do pts with PTSD who get gastric bypass feel better?

    • RM

      That is an excellent question!
      And, in fact, an avenue of investigation I proposed during my defense but in the reverse direction: is there a lower incidence of PTSD in the population of patients who have undergone gastric bypass and, specifically, roux-en-y gastric bypass which removes the majority of the ghrelin producing cells.

      • CRH

        Cool thanks. My husband had a stressful childhood (you can insert details) and has a very high stress job. He had roux-en-y about 6 weeks ago. He is exhausted and feels less sharp at work (multifactorial obviously) but I think some of it is lack of this key stress hormone. I’m hoping in the long run it will be beneficial to his mental health (again clearly multifactorial given the concurrent weight loss). Keep us posted and good luck with your research!

        • Bonnie Nolamama Dwyer

          I had LAP-band in 2004 & developed complex PTSD in 2009.

          • RM

            Firstly, Bonnie, I am so sorry to hear that you have PTSD. I do hope that you are recovering and getting all the help that you can. There are many resources available.

            To reconcile CRH’s statement and yours within the scientific question at hand: lap band does not remove the cells of the stomach that produce ghrelin. The roux-en-y procedure does. Those patients that undergo lap band will, therefore, have an intact ghrelin system afterwards whereas those who undergo roux-en-y would not. Does that make sense?

  • David Emerson

    Many people with severe or complex PTSD have been terribly hurt, abused, and neglected by other people including their “caretakers” or they have engaged in war time atrocities that most people would not even want to know about or they have been tortured or sold into slavery while other children are watching Sesame Street. No medication will “block” or “erase” these kinds of experiences. We need to think about PTSD, especially very complex trauma, in a much more holistic, humanistic perspective and not as something that can be solved in a lab.

    • Susan Pease Banitt

      True, although there is a holistic implication to this finding. Traditional Chinese Medicine (TCM) has always considered PTSD and stress disorders as a digestive disorder that is treated along the stomach meridian. This will help us connect the dots.

  • Isobel Clinton

    This may well lead to a new form of ameliorating the pain of anxiety and depression. But the paragraphs about what the experimenters do to the rats to find out have left me depressed and anxious.

  • TKL

    I’m stressed I can’t eat, and I lose a ton of weight – I have PTSD

  • Gloria Doan

    Could this also be a key to losing weight?

    • MITBeta

      It could certainly explain “stress eating”.

      • RM

        Exactly! (see above comment)

    • TKL

      If it is, for those who probably have it in their system I would say it’s probably not a good way to do it! I wind up under weight when stress fires up my PTSD