In a struggle that probably sounds familiar to dieters everywhere, at the very least Caenorhabditis elegans (C. elegans) The more a worm eats, the slower it loses fat. Now, scientists at Scripps Research have discovered why: A small molecule produced by the worms’ guts during fasting travels to the brain to block a fat-burning signal during this time.
Although the exact molecule they identified in the worms has not yet been studied in humans, the new work helps scientists better understand the complex communication between the gut and the brain. It may also shed light on why fasting (not eating for set periods of time) has benefits that are independent of the amount of calories a person consumes. The new study was published in Nature Communicationson August 11, 2024.
“We have discovered for the first time that fasting transmits information to the brain beyond the simple withdrawal of calories,” said Scripps research professor of neuroscience Supriya Srinivasan, PhD, senior author of the new study.. “These findings make me wonder whether there are molecules produced in the guts of other animals, including mammals, that explain some of the health problems associated with fasting.”
Researchers have long known that the brain controls the production and breakdown of fats in humans, other mammals, and model organisms such as C. elegansIn 2017, Srinivasan’s group identified FLP-7, a brain hormone that triggers fat burning in the roundworm gut. C. elegans They have no sensory nerves in their guts, so scientists have struggled to determine the reverse communication pathway: how does the gut send signals to the brain?
“We knew that altering the metabolic state of the gut could change the properties of neurons in the brain, but it was very mysterious how this actually happened,” Srinivasan says.
In the new work, Srinivasan and his colleagues eliminated more than 100 signaling molecules from C. elegans The researchers examined the guts one at a time and measured their impact on FLP-7 production in the brain. They found one molecule that had a big effect on FLP-7: a form of insulin known as INS-7. In humans, insulin is best known as the hormone produced by the pancreas that controls blood sugar levels. But this insulin molecule was produced by gut cells and also affected fat metabolism through the brain.
“When we discovered that it was an insulin, we thought it was paradoxical,” Srinivasan recalls. “Insulin is very well studied in mammals and there was no precedent for an insulin molecule performing this function.”
However, when the group investigated how INS-7 affected FLP-7-producing brain cells, they found that it did not activate insulin receptors (as all previously discovered insulin molecules do), but instead blocked the insulin receptor. In turn, this blockage triggered a cascade of other molecular events that eventually caused the brain cells to stop producing FLP-7.
“INS-7 is basically a signal coming from the gut that tells the brain not to burn any more fat stores right now because there’s no food coming in,” Srinivasan explains.
Previous studies have shown that periods of fasting can influence the body in a variety of ways, but the mechanisms for those changes were unclear. The new study points to a way an empty gut may send signals to the brain, which could have a variety of health impacts beyond fat.
The new findings, Srinivasan says, help explain how the brain and digestive system communicate back and forth to control metabolism based on food availability. More research is needed to figure out which specific pathways are involved in the new gut-to-brain signals in mammals. Compounds that mimic gut hormones, such as semaglutide, commonly known under brand names like Ozempic, Wegovy, and Rybelus, have recently emerged as popular ways to manage obesity and diabetes, so the new gut peptides could add to this class of drugs. Srinivasan is also planning experiments to investigate how gut peptides can help control obesity and diabetes. C. elegans Gut cells are activated to produce INS-7 during fasting and what types of brain cells are affected by the molecule.
This work was supported by the National Institutes of Health (R01 DK124706 and R01 AG056648).