The emergency button

A stress receptor in the brain is found to regulate metabolic responses to stressful situations differently in male and female mice

May 25, 2016

In the face of stress, our body diverts metabolic resources to its emergency response. It has been thought that the sympathetic nervous system – the body’s instinctive system for reacting to stress – directs this activity, but now researchers at the Max Planck Institute of Psychiatry in Munich show that certain neurons in the brain have a surprising role to play. The findings, which recently appeared in Cell Metabolism, may aid the development of better drugs for stress-related pathologies such as eating disorders.

Alon Chen, Director of the Neurobiology Department of Stress Neurobiology and Neurogenetics, together with Yael Kuperman from the Max Planck – Weizmann Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics, focused on an area of the brain called the hypothalamus. This brain area has a number of functions, among them helping the body adjust to stressful situations, controlling hunger and satiety, and regulating blood glucose and energy expenditure – as it were the emergency button within the brain.

When stress hits, cells in the hypothalamus step up the activation of a receptor on their surface called CRFR1. It was known that this receptor contributes to the rapid activation of the autonomous nervous system – increasing heart rate, for example. But since this area of the brain also regulates the body’s energy balance, the team thought that the CRFR1 receptor might play a role in this, as well.

Chen and his group characterized cells in a certain area of the hypothalamus, finding that the receptor is expressed in around half of the cells that arouse appetite and suppress energy expenditure. These cells comprise one of two main populations in the hypothalamus – the other promotes satiety and energy expenditure. “This was a bit of a surprise,” says Chen, “as we had instinctively expected the receptor to be expressed on the cells that suppress hunger.”

Continuing their investigation, the researchers removed the CRFR1 receptors only from the cells that arouse appetite in the hypothalamus and then observed how this affected the mice’s bodily functions. At first, they did not see any significant changes, confirming that this receptor is reserved for stressful situations. However, when they exposed the mice to stress – cold or hunger – they got another surprise.

When exposed to cold, the sympathetic nervous system activates a unique type of fat called brown fat, which produces heat to maintain the body’s internal temperature. When the receptor in the brain was removed, body temperature dropped dramatically – but only in female mice. Even afterwards their temperatures failed to stabilize, while male mice showed hardly any change.

Fasting produced a similarly drastic response in the female mice. Normally when food is scarce, the brain sends a message to the liver to produce glucose, conserving a minimum level in the blood. But when food was withheld from female mice missing the CRFR1 receptor, the amount of glucose their livers produced dropped significantly. In hungry male CRFR1-deficient mice, like those exposed to cold, the metabolism was barely affected.

“We discovered that the receptor has an inhibitory effect on the nerve cells, and this is what allows activation of the sympathetic nervous system,” says Matthias Eder, from the Max Planck Institute of Psychiatry, who also participated in this study.

In addition to revealing exactly how this receptor works and how it contributes to the stress response, the findings show that male and females exhibit significant differences in their metabolic response to stressful challenges. Indeed, the fact that the receptor is known to suppress eating may help explain why women are much more prone to eating disorders than men.

These findings could aid in developing psycho-pharmaceutical treatments, especially since drugs are able to enter the hypothalamus with relative ease.  Indeed, several pharmaceutical companies have already begun developing drugs to block the CRFR1 receptor for the possible treatment of anxiety disorders and depression. The scientists caution, however, that because the cells are involved in energy balance, blocking the receptor could turn out to have side effects such as weight gain.

Weizmann Institute

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