Research shows how hormone can reverse fatty liver disease

OKLAHOMA CITY – A pioneering research study published today in Cell Metabolism details how the hormone FGF21 (fibroblast growth factor 21) can reverse the effects of fatty liver disease in mice. The hormone works primarily by signaling the brain to improve liver function.

University of Oklahoma researcher Matthew Potthoff, Ph.D., is the lead author of the study, which provides valuable insight about the mechanism of action of the hormone, which is a target for a new class of highly anticipated drugs that are in Phase 3 clinical trials.

“Fatty liver disease, or MASLD (metabolic dysfunction-associated steatotic liver disease), is a buildup of fat in the liver. It can progress to MASH (metabolic dysfunction-associated steatohepatitis) during which fibrosis and, ultimately, cirrhosis can occur. MASLD is becoming a very big problem in the United States, affecting 40% of people worldwide, and there is currently only one treatment approved by the Food and Drug Administration to treat MASH. A new class of drugs, based on FGF21 signaling, is showing good therapeutic benefits in clinical trials, but until now, the mechanism for how they work has been unclear,” said Potthoff, a professor of biochemistry and physiology at the University of Oklahoma College of Medicine and deputy director of OU Health Harold Hamm Diabetes Center.

The study’s results demonstrated that FGF21 was effective at causing signaling in the model species that changed the liver’s metabolism. In doing so, the liver’s fat was lowered and the fibrosis was reversed. The hormone also sent a separate signal directly to the liver, specifically to lower cholesterol.

“It’s a feedback loop where the hormone sends a signal to the brain, and the brain changes nerve activity to the liver to protect it,” Potthoff said. “The majority of the effect comes from the signal to the brain as opposed to signaling the liver directly, but together, the two signals are powerful in their ability to regulate the different types of lipids in the liver.”

Similar to the family of weight loss drugs known as GLP-1s (glucagon-like peptide 1), which help regulate blood sugar levels and appetite, FGF21 acts on the brain to regulate metabolism. In addition, both are hormones produced from peripheral tissues – GLP-1 from the intestine and FGF21 from the liver – and both work by sending a signal to the brain.

“It is interesting that this metabolic hormone/drug works primarily by signaling to the brain instead of to the liver directly, in this case,” he said. “FGF21 is quite powerful because it not only led to a reduction of fat, but it also mediated the reversal of fibrosis, which is the pathological part of the disease, and it did so while the mice were still eating a diet that would cause the disease. Now, we not only understand how the hormone works, but it may guide us in creating even more targeted therapies in the future.”

###

About the Project

The paper, “FGF21 reverses MASH through coordinated actions on the CNS and liver,” can be found at https://doi.org/10.1016/j.cmet.2025.04.014. Additional authors are Jesse Rose, Donald Morgan, Kamal Rahmouni and Andrew Sullivan from the University of Iowa Carver College of Medicine, and Xiaorong Fu, Melissa Inigo-Vollmer, Shawn Burgess and David Meyerholz from the University of Texas Southwestern Medical Center.

About the University of Oklahoma

Founded in 1890, the University of Oklahoma is a public research university with campuses in Norman, Oklahoma City and Tulsa. As the state’s flagship university, OU serves the educational, cultural, economic and health care needs of the state, region and nation. In Oklahoma City, OU Health Sciences is one of the nation’s few academic health centers with seven health profession colleges located on the same campus. OU Health Sciences serves approximately 4,000 students in more than 70 undergraduate and graduate degree programs spanning Oklahoma City and Tulsa and is the leading research institution in Oklahoma. For more information about OU Health Sciences, visit www.ouhsc.edu.