University of Oklahoma scientists report that the hormone FGF21 reduces body weight in obese mice by acting on a hindbrain pathway—centered on the nucleus of the solitary tract and area postrema—that relays signals to the parabrachial nucleus. The team says the mechanism overlaps anatomically with brain regions implicated in GLP-1 drugs, but appears to promote weight loss mainly by increasing metabolic rate rather than primarily suppressing food intake.
A research group led by Matthew Potthoff, Ph.D.—a professor of biochemistry and physiology in the University of Oklahoma (OU) College of Medicine and deputy director of the OU Health Harold Hamm Diabetes Center—has identified a neural circuit in the hindbrain that is required for the weight-loss effects of fibroblast growth factor 21 (FGF21) in mice. The work was published in Cell Reports, according to an OU Health Campus news release.
In the study, the researchers report that FGF21 signals to β-klotho (KLB)-expressing neurons in two hindbrain regions—the nucleus of the solitary tract (NTS) and the area postrema (AP)—and that these neurons are necessary and sufficient for FGF21’s effects on energy expenditure and weight loss.
Potthoff said the location of the signal was unexpected. “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,” he said.
The OU release describes the pathway as a relay from the NTS and AP to the parabrachial nucleus, a connection the researchers say is needed for FGF21 to produce its metabolic benefits. “This brain circuit seems to be mediating the effects of FGF21,” Potthoff said.
While the hindbrain regions highlighted in the study overlap with areas often discussed in connection with GLP-1–based obesity medicines, the researchers emphasized a difference in the dominant physiological effect described in their work: GLP-1 medicines are commonly characterized as reducing food intake, whereas FGF21’s weight-loss effect in this report is linked to increased metabolic rate and energy expenditure.
FGF21-based drugs are already being explored clinically for metabolic dysfunction–associated steatohepatitis (MASH), a form of fatty liver disease, the OU release said. It also noted that FGF21 analogs have been associated with side effects such as gastrointestinal issues and, in some cases, bone loss.
The study focused on body-weight regulation in mice, and Potthoff said further research will be needed to determine whether the same hindbrain circuit also explains FGF21’s potential benefits in MASH.
