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Scientists have discovered how a naturally occurring hormone can reverse obesity in mice, and the answer lies in the brain. Researchers at the University of Oklahoma found that the hormone works by sending signals to a brain region that helps control metabolism and appetite. This is the same general area targeted by widely used GLP-1 weight loss drugs. The findings were published in the journal Cell Reports.
The hormone, known as FGF21 (fibroblast growth factor 21), has already attracted attention as a potential target for new therapies. Drugs designed to act on this pathway are currently being tested in clinical trials for MASH (metabolic dysfunction-associated steatohepatitis), a serious form of fatty liver disease.
Lead researcher Matthew Potthoff, Ph.D., and his team focused on understanding exactly how FGF21 produces its effects. Their results show that the hormone acts through the hindbrain, which is located in the lower back part of the brain.
Unexpected Brain Region Revealed
“In our previous studies, we found that FGF21 signals to the brain instead of the liver, but we didn’t know where in the brain,” said Potthoff, a professor of biochemistry and physiology in the OU College of Medicine and deputy director of OU Health Harold Hamm Diabetes Center. “We thought we would find that it signaled to the hypothalamus (which is widely implicated in body weight regulation), so we were very surprised to discover that the signal was to the hindbrain, which is where the GLP-1 analogs are believed to act.”
More specifically, FGF21 interacts with two parts of the hindbrain called the nucleus of the solitary tract (NTS) and the area postrema (AP). These regions then communicate with another brain structure known as the parabrachial nucleus. This chain of signaling is essential for the hormone’s ability to influence metabolism and reduce body weight.
Brain Circuit Drives Fat Burning Effects
“This brain circuit seems to be mediating the effects of FGF21,” Potthoff said. “We hope that by identifying the specific circuit, it can help in the creation of more targeted therapies that are effective without negative side effects. FGF21 analogues have side effects like gastrointestinal issues and, in some cases, bone loss.”
Although FGF21 and GLP-1 drugs affect similar areas of the brain, they work in very different ways. GLP-1 medications reduce appetite and food intake, while FGF21 increases metabolic activity, helping the body burn more energy and lose weight.
Potential for Future Obesity and Liver Disease Treatments
Potthoff and his team are optimistic that this research could lead to new treatments for both obesity and MASH.
“While this study focused on the mechanism of FGF21 to reduce body weight, additional studies are necessary to examine whether this circuit also mediates the ability of FGF21 and FGF21 analogues to reverse MASH,” he said.
