Cedars-Sinai Investigators Identify a Brain Circuit in Mice That Suppresses Feeding and Boosts Energy Expenditure in Response to Stress—Especially in Females

A Cedars-Sinai study has identified a group of brain cells in laboratory mice that regulate stress-induced feeding and calorie expenditure, with a more pronounced effect in females than in males.

The discovery, published in the peer-reviewed journal Nature Communications, has given investigators a potential target for treating stress-induced eating disorders in women.

“These results are very exciting because they help us understand an important aspect of how stress is regulated,” said Celine Riera, PhD, assistant professor of Biomedical Sciences and Neurology at Cedars-Sinai and senior author of the study. “We hope to leverage this knowledge to help develop treatments for anxiety-related eating disorders.”

The study is the first to examine specific neurons responsible for the body’s metabolic response to stress, Riera said, and the first to compare results in male and female laboratory mice to identify sex-based differences in the brain’s stress response.

Riera and fellow investigators induced stress by exposing both male and female laboratory mice to predator odor. Both male and female mice were more active and ate less when exposed to stress, but the effect was more pronounced and lasted longer in female mice than in male mice.

Investigators, including Predrag Jovanovic, PhD, then used two different methods to determine which brain cells were responsible for this reaction.

The investigators recorded which neurons were expressing high levels of a protein called c-Fos, which indicated they were activated by the scent. The investigators then traced the connections of the activated neurons, using a virus that makes a fluorescent probe, from the part of the brain receiving scent information from the nose to the neurons activated in another part of the brain by the scent.

Both experiments pointed to the dorsomedial hypothalamus, a brain region established as important for the regulation of feeding and energy expenditure. The region is known to contain neurons that signal when the body is full, and neurons that regulate body temperature, but this study pinpointed a third type of neuron in the region.  

“We're showing for the first time that there is another population of neurons,” Riera said. “They are called cholecystokinin-expressing, or CCK, neurons, and they play a role in metabolism by suppressing feeding and increasing energy expenditure in response to stress or fear.”

The team next plans to examine these same neurons in the context of obesity, Riera said.

“We want to investigate whether chronically activating these neurons will promote weight loss, and whether that effect is stronger in females compared with males,” she said. “We’re hoping we can confirm these neurons as a therapeutic target for treating metabolic disorders.”

Scientists and health experts are trying to learn more about why obesity rates worldwide continue to rise, and why the prevalence of obesity is higher in women than in men, Riera said.

“Male-female differences in response to stress and eating are poorly understood from a neurological perspective,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This line of inquiry and the focus of these investigators on including females in their work offers a potential key to better understanding these issues–and possibly improving the health of millions.”

Funding: The study was funded by American Diabetes Association Pathway to Stop Diabetes Grant number 1-15-INI-12, the Klingenstein-Simons foundation, the Larry L. Hillblom Foundation fellowship, and the Cedars-Sinai Center for Research in Women’s Health and Sex Differences.