By doing tests on mice fed on a calorie restricted diet, US researchers have discovered that ghrelin, a hormone that increases when people don’t eat, may defend against symptoms of depression or anxiety brought on by stress.

The research is the work of scientists led by senior author Dr Jeffrey Zigman, assistant professor of internal medicine and psychiatry at the University of Texas (UT) Southwestern Medical Center in Dallas. It was published online on 15th June 2008 in the journal Nature Neuroscience.

“Our findings in mice suggest that chronic stress causes ghrelin levels to go up and that behaviors associated with depression and anxiety decrease when ghrelin levels rise,” said Zigman, adding that:

“An unfortunate side effect, however, is increased food intake and body weight.”

Lead author and instructor of psychiatry at UT Southwestern, Dr Michael Lutter, said:

“Our findings support the idea that these hunger hormones don’t do just one thing; rather, they coordinate an entire behavioral response to stress and probably affect mood, stress and energy levels.”

Scientists like Zigman and colleagues already knew that fasting causes the gut to produce ghrelin, which is involved in sending hunger signals to the brain, and this has led them to suggest blocking ghrelin as an approach to weight control.

But this new study shows that if you do that, it could interfere with the body’s natural way of dealing with anxiety and depression.

For the study, Zigman and his team put “wild type” (ie not genetically altered in any way) mice on a calorie restricted diet for 10 days, which led to a four-fold increase in their ghrelin levels. Stress tests involving mazes and forced swims showed that the calorie restricted mice had reduced symptoms of anxiety and depression compared to control couterparts that had been allowed unrestricted access to food.

The researchers then bred genetically altered mice whose bodies did not respond to ghrelin and fed them a calorie restricted diet as well, but under stress tests their depression and anxiety symptoms stayed high; there was no anti-depression or anti-anxiety effect as there had been in the wild type mice on the low calorie diet.

Finally, Zigman and colleagues did a third test, this time to explore social stress where normal wild type and genetically altered mice were exposed to aggressive “bully” mice every day (an approach often used to study parallels of depression in humans).

Under stress conditions both types of mice had raised ghrelin that lasted for up to four weeks after being bullied for the last time, but the mice that had been genetically altered not to respond to gherlin showed more social avoidance behaviour and ate less than the non-altered mice, suggesting they had more depression symptoms.

A possible explanation could be the survival advantage that is gained from such an effect over countless generations of evolution where the main priority is getting enough food to avoid starving to death. Zigman suggested that hunter gatherers needed to remain calm in order to hunt successfully (or they could end being someone else’s meal). Perhaps ghrelin induced by hunger leading to anti-anxiety gave them the edge over their competitors.

These findings might also explain what happens in conditions like anorexia nervosa said Lutter:

“We’re very interested to see whether ghrelin treatment could help people with anorexia nervosa, with the idea being that in a certain population, calorie restriction and weight loss could have an antidepressant effect and could be reinforcing for this illness.”

Zigman, Lutter and colleagues hope to continue with their research and look at the areas of the brain where ghrelin could be causing these antidepressant-like effects.

“The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress.”
Michael Lutter, Ichiro Sakata, Sherri Osborne-Lawrence, Sherry A Rovinsky, Jason G Anderson, Saendy Jung, Shari Birnbaum, Masashi Yanagisawa, Joel K Elmquist, Eric J Nestler & Jeffrey M Zigman
Nature Neuroscience Published online 15 June 2008.
DOI: 10.1038/nn.2139

Click here for Abstract.

Sources: Nature Neuroscience press release and abstract.

Written by: Catharine Paddock, PhD