University of Oklahoma researchers have identified the specific brain regions through which fibroblast growth factor 21 (FGF21) exerts its anti-obesity effects, revealing a signalling pathway distinct from GLP-1 therapies that could inform more targeted metabolic disease treatments.
A naturally occurring hormone that reverses obesity in mice may work by targeting a key brain region involved in appetite and metabolism, according to new research from the University of Oklahoma.
Insight into a promising hormone
The study highlights the potential of fibroblast growth factor 21 (FGF21), a hormone already being explored in drug development.
Researchers say the findings could help advance treatments for both obesity and metabolic dysfunction-associated steatohepatitis, a serious form of fatty liver disease. Drugs targeting the FGF21 pathway are currently undergoing clinical trials for the condition.
How the hormone works
Led by Matthew Potthoff, the research team discovered that FGF21 exerts its effects by signalling to the hindbrain, the lower back region of the brain responsible for regulating essential bodily functions.
Earlier studies had shown that FGF21 communicates with the brain rather than the liver but the exact location of this interaction was unknown.
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
“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 at the University of Oklahoma College of Medicine and Deputy Director of the OU Health Harold Hamm Diabetes Center. “We thought we would find that it signalled 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.”
Key brain pathways identified
The study found that FGF21 specifically targets two regions within the hindbrain: the nucleus of the solitary tract and the area postrema. These areas then relay signals to another part of the brain known as the parabrachial nucleus.
This signalling pathway appears to be essential for the hormone’s ability to regulate metabolism and reduce body weight.
“This brain circuit seems to be mediating the effects of FGF21,” said Potthoff. “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.”
Comparison with existing treatments
Although FGF21 acts on the same general brain region as GLP-1-based drugs, the mechanisms differ. GLP-1 treatments primarily reduce food intake, while FGF21 increases metabolic rate, enabling the body to burn more energy and lose weight.
Although FGF21 acts on the same general brain region as GLP-1-based drugs, the mechanisms differ
This distinction could make FGF21-based therapies a valuable alternative or complement to already existing approaches.
Looking ahead
While the current study focused on how FGF21 influences body weight, further research will be needed to determine whether the same brain circuit also plays a role in reversing metabolic dysfunction-associated steatohepatitis.
Scientists hope that a deeper understanding of this pathway will ultimately lead to more precise and effective treatments for obesity and related metabolic diseases.
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