A newly studied hormone is revealing an unexpected connection between metabolism and the brain.
A hormone that can reverse obesity in mice is offering new clues about how the brain controls body weight. Researchers at the University of Oklahoma found that FGF21 (fibroblast growth factor 21) acts on a key brain region tied to appetite and metabolism, the same general area influenced by widely used GLP-1 drugs. Their findings were published in Cell Reports.
Unlike many metabolic signals that act on organs such as the liver or fat tissue, FGF21 appears to work primarily through the brain.
Interest in FGF21 is already growing, with drugs targeting its pathway under clinical investigation for MASH (metabolic dysfunction-associated steatohepatitis), a serious form of fatty liver disease linked to obesity and insulin resistance.
How FGF21 Works in the Brain
The study, led by Matthew Potthoff, Ph.D., identifies the hindbrain as the hormone’s key site of action. This region plays a central role in regulating basic functions such as hunger, energy balance, and nausea.
“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 targets areas of the hindbrain called the nucleus of the solitary tract (NTS) and the area postrema (AP). These regions communicate with another structure known as the parabrachial nucleus. This signaling pathway is required for FGF21 to produce its metabolic effects and reduce body weight.
Implications for Treatment Development
“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 analogs have side effects like gastrointestinal issues and, in some cases, bone loss.”
Although FGF21 and GLP-1 influence the same general brain region, they work in different ways. GLP-1 lowers food intake, while FGF21 raises metabolic rate, increasing energy use and promoting weight loss.
Potthoff ultimately hopes this research will contribute 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 analogs to reverse MASH,” he said.
Reference: “Pharmacological administration of FGF21 reverses obesity through a parabrachial-projecting neuron population in the hindbrain” by Yunfan Lin, Kristin E. Claflin, Iltan Aklan, Donald A. Morgan, Andrew I. Sullivan, Michael C. Rudolph, Kamal Rahmouni and Matthew J. Potthoff, 31 March 2026, Cell Reports.
DOI: 10.1016/j.celrep.2026.117093
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