Scientists at The Scripps Institute have discovered a molecule produced by the guts of roundworms that sends signals to the brain to slow fat loss when food is not available. The new work helps scientists better understand the complex communication between the gut and the brain. It may also explain why fasting (not eating for specific periods of time) has benefits that go beyond the number of calories a person consumes.
Why do roundworms and their intestines matter to us?
Although the molecule identified in the worms has not yet been studied in humans, it may give us insight into what might be going on in our own bodies. Thousands of scientists work full-time around the world studying the biology of roundworms. Between October 1994 and January 1995, 73 scientific articles about this creature appeared in international scientific journals.
Roundworms are largely primitive organisms, yet they share many of the basic biological characteristics that are central to human biology. Roundworms are single cells that undergo a complex process of development, beginning with embryonic division, and proceeding through morphogenesis and growth to adulthood. They have a nervous system with a “brain.” They exhibit behavior and are even capable of rudimentary learning. Thus, roundworms provide the researcher with the ideal compromise between complexity and manipulatory ability.
Dieters’ struggles
In a conflict that may sound familiar to dieters everywhere, the less a roundworm eats, the less fat it loses. Now, scientists at The Scripps Institute have discovered why: A small molecule produced by the worms’ guts during fasting travels to the brain to block the fat-burning signal during this period. The findings are published in Nature Communications on August 11, 2024.
“We’ve discovered for the first time that fasting conveys information to the brain beyond just calorie withdrawal,” says Supriya Srinivasan, PhD, professor of neuroscience at The Scripps Institute and lead author of the study. “These findings make me wonder if there are molecules produced in the gut of other animals, including mammals, that explain some of the health outcomes associated with fasting.”
How does the gut tell the brain what is happening around it?
Researchers have known that the brain controls the production and breakdown of fats in humans, other mammals, and model organisms like roundworms. In 2017, Srinivasan’s group identified a brain hormone called FLP-7 that stimulates fat burning in the roundworm’s gut. However, roundworms don’t have sensory nerves in their gut, so scientists have struggled to pinpoint the reverse communication pathway: How does the gut send signals to the brain?
“We knew that changing the metabolic state of the gut could change the properties of neurons in the brain, but it was a mystery how this actually happened,” Srinivasan says.
In this new work, Srinivasan and colleagues removed more than 100 signaling molecules from the gut of roundworms, one by one, and measured their effect on the brain’s production of FLP-7.
Insulin is not like other insulins
They found that one of the molecules had a significant effect on FLP-7, a type of insulin known as INS-7 in humans. Insulin is primarily a hormone produced by the pancreas to control blood sugar levels. But the new insulin molecule was instead produced by cells in the gut and also affected metabolism via the brain.
“When we first discovered that this was an insulin molecule, we thought it was incredible,” Srinivasan recalled, according to EurekAlert. “Insulin is well-studied in mammals, and there was no precedent for an insulin molecule playing this role.”
However, when the group looked at how INS7 affected the brain cells that produce FLP-7, they found that it did not activate insulin receptors—as all previously discovered insulin molecules do—but rather worked by blocking insulin receptors. Instead, this blocking set off a chain of molecular events that eventually caused the brain cells to stop producing FLP-7.
“The INS7 molecule is basically a signal coming from the gut telling the brain not to burn more fat stores right now because there is no food coming,” Srinivasan explains.
Previous studies have shown that periods of fasting can affect the body in a variety of ways, but the mechanisms that cause these changes have been unclear. The new study suggests a way in which an empty gut can send signals to the brain, which could lead to a variety of health effects that go beyond fat.
What’s next?
The new findings help explain how the brain and gut communicate in both directions to control metabolism based on food availability, Srinivasan says. More research is needed to uncover the specific pathways involved in the new gut-to-brain signaling in mammals. The new gut peptides could add to the existing class of drugs that mimic gut hormones, such as semaglutide. Srinivasan also plans experiments to explore how gut cells in roundworms are stimulated to produce INS7 during fasting, and which types of brain cells are affected by the molecule.