Many dieters can relate to the observation that when a Caenorhabditis elegans (C. elegans) worm consumes less food, it loses fat at a slower pace. Recent research from Scripps Research has uncovered a reason behind this phenomenon: a tiny molecule created in the worms’ intestines when they fast sends a signal to the brain, inhibiting fat burning during this period.
While the specific molecule researchers identified in the worms hasn’t yet been examined in humans, this study enhances our understanding of the intricate communication between the gut and the brain. It may also illuminate why intermittent fasting—skipping meals for specific intervals—can provide advantages unrelated to caloric intake. The findings were published in Nature Communications on August 11, 2024.
“For the first time, we discovered that fasting conveys messages to the brain aside from just calorie deficit,” stated Supriya Srinivasan, PhD, Professor of Neuroscience at Scripps Research and the lead researcher on the study. “These results lead me to ponder whether other animals, including mammals, produce gut molecules that could clarify some health benefits linked to fasting.”
Researchers have long recognized that the brain regulates the synthesis and breakdown of fats in humans, other mammals, and laboratory organisms like C. elegans. Back in 2017, Srinivasan’s team identified FLP-7, a brain hormone that stimulates fat burning in the gut of roundworms. However, because C. elegans lack sensory nerves in their intestines, pinpointing the signaling pathway from the gut to the brain has proven difficult.
“We understood that modifying the gut’s metabolic state could alter neuron functions in the brain, but it remained unclear how this occurred,” Srinivasan noted.
In this new research, Srinivasan and her team systematically eliminated over 100 signaling molecules from the intestines of C. elegans one by one and observed their effects on the brain’s FLP-7 production. They discovered that one specific molecule notably influenced FLP-7 levels: a type of insulin called INS-7. In humans, insulin is primarily recognized as the hormone produced by the pancreas that regulates blood sugar. However, in this case, the insulin-like molecule was produced by gut cells, influencing fat metabolism through the brain.
“Initially, we found it paradoxical that this was an insulin,” Srinivasan reflected. “Insulin is so extensively researched in mammals, and nothing had suggested an insulin molecule functioning in this way before.”
When the researchers examined how INS-7 affected the brain cells that produce FLP-7, they discovered that it didn’t activate insulin receptors, which is typical for known insulin molecules, but instead blocked the insulin receptor. This inhibition triggered a series of molecular events that ultimately caused brain cells to stop producing FLP-7.
“INS-7 serves as a signal from the intestines to the brain, indicating that fat stores should not be used at the moment since there’s no incoming food,” Srinivasan elaborated.
Previous research has indicated that fasting can lead to various bodily changes, but the underlying mechanisms have often remained elusive. This study paves the way to understanding one method through which the empty gut can communicate with the brain, potentially impacting various health aspects beyond fat loss.
According to Srinivasan, the findings clarify the bidirectional communication between the brain and digestive system in regulating metabolism based on food availability. Further investigations are necessary to identify the specific pathways involved in these new gut-to-brain signals in mammals. Recently, compounds designed to mimic gut hormones—such as semaglutide, known by brand names like Ozempic, Wegovy, and Rybelus—have gained popularity as treatments for obesity and diabetes, so discovering new gut peptides could enhance this drug class. Srinivasan also plans to conduct experiments to explore how C. elegans gut cells are stimulated to produce INS-7 during fasting and which brain cell types are impacted by this molecule.
This research received support from the National Institutes of Health (R01 DK124706 and R01 AG056648).
