Dr. Yael Kuperman began this study as part of her doctoral research in the lab of Prof. Alon Chen of the Department of Neurobiology. Dr. Kuperman, presently a staff scientist in the Veterinary Resources Department, Prof. Chen, and research student Meira Weiss focused on an area of the brain called the hypothalamus, which has a number of functions, among them helping the body adjust to stressful situations, controlling hunger and satiety, and regulating blood glucose and energy production.
When stress hits, cells in the hypothalamus step up production of a receptor called CRFR1. It was known that this receptor contributes to the rapid activation of a stress-response sympathetic nerve network – increasing heart rate, for example. But since this area of the brain also regulates the body’s exchange of materials, the team thought that the CRFR1 receptor might play a role in this, as well.
Prof. Chen and his group characterized the 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 consumption. These cells comprise one of two main populations in the hypothalamus – the second promotes satiety and the burning of energy. “This was a bit of a surprise,” says Dr. Kuperman, “as we would instinctively expect the receptor to be expressed on the cells that suppress hunger.”
To continue investigating, the researchers removed the CRFR1 receptor in mice from just the cells that arouse appetite in the hypothalamus, and then observed how this affected the animals’ bodily functions. At first, the team did not see any significant changes, confirming that this receptor is saved for stressful situations. But 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 was removed, the body temperature dropped dramatically – but only in the female mice. Their temperatures failed to stabilize even afterward the stressor was removed, 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, the result was similar to the effects of exposure to cold: the exchange of materials in their bodies was barely affected.
“We discovered that the receptor has an inhibitory effect on the cells, and this is what activates the sympathetic nervous system,” says Dr. Kuperman.
Among other things – revealing exactly how this receptor works and how it contributes to the stress response – the findings show that male and female bodies may exhibit significant differences in the ways that materials are exchanged under stress. Indeed, the fact that the receptor suppresses hunger in females may help explain why women are much more prone to eating disorders than men.
Because drugs can enter the hypothalamus with relative ease, the findings could be relevant to the development of treatments for regulating hunger or stress responses, including anxiety disorders or depression. Indeed, several pharmaceutical companies have already begun developing psychiatric drugs to block the CRFR1 receptor. The scientists caution, however, that because the cells are involved in the exchange of materials, blocking the receptor could turn out to have such side effects as weight gain.
Prof. Alon Chen’s research is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Irving I Moskowitz Foundation; the European Research Council; the estate of Tony Bieber; and the Ruhman Family Laboratory for Research in the Neurobiology of Stress.The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide.
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