Scientists have discovered how a naturally occurring hormone can reverse obesity in mice. The answer lies in the brain. Researchers at the University of Oklahoma have discovered that this hormone works by sending signals to areas of the brain that help control metabolism and appetite. This is the same general area targeted by widely used GLP-1 weight loss drugs. The research results were published in a magazine cell report.
This hormone, known as FGF21 (fibroblast growth factor 21), has already attracted attention as a potential target for new treatments. Drugs designed to act on this pathway are currently being tested in clinical trials for MASH (metabolic dysfunction-associated steatohepatitis), a severe form of fatty liver disease.
Principal investigator Dr. Matthew Potthoff and his team focused on understanding exactly how FGF21 produces its effects. Their results show that this hormone acts through the hindbrain, located at the bottom of the brain.
Unexpected brain regions revealed
“Previous studies showed that FGF21 signals to the brain rather than the liver, but we didn’t know where in the brain it was,” said Potthoff, professor of biochemistry and physiology in the OU School of Medicine and associate director of the OU Health Harold Hamm Diabetes Center. “We expected to find that it was sending a signal to the hypothalamus (which is widely involved in weight regulation), so we were very surprised to find that it was sending a signal to the hindbrain, where GLP-1 analogues are thought to act.”
More specifically, FGF21 interacts with two parts of the hindbrain called the solitary tract nucleus (NTS) and the area hindbrain (AP). These areas communicate with another brain structure known as the parabrachial nucleus. This signaling chain is essential to the hormone’s ability to influence metabolism and reduce weight.
Brain circuits promote fat burning effects
“This brain circuit appears to mediate the effects of FGF21,” Potthoff said. “We hope that identifying specific circuits will help us develop more targeted treatments that are effective without negative side effects. FGF21 analogs have side effects such as gastrointestinal disturbances and, in some cases, bone loss.”
Although FGF21 and GLP-1 drugs affect similar areas of the brain, they act in very different ways. GLP-1 drugs reduce appetite and food intake, while FGF21 increases metabolic activity, helping the body expend more energy and lose weight.
Potential future treatments for obesity and liver disease
Potthoff and his team are optimistic that this research could lead to new treatments for both obesity and MASH.
“Although this study focused on the mechanism of FGF21 to reduce body weight, additional studies are needed to examine whether this circuit also mediates the ability of FGF21 and FGF21 analogs to reverse MASH,” he said.
