Researchers at the University of Oklahoma have found that a naturally occurring hormone may offer a new way to reverse obesity without the need for calorie restriction.

The study, published in the journal Cell Reports, focused on fibroblast growth factor 21, known as FGF21, which appears to communicate with a region of the brain that regulates metabolism and appetite.

According to a university press release, FGF21 “appears to work by signaling to a brain region involved in metabolism and appetite regulation, the same area targeted by the popular GLP-1 drugs.”

FGF21 is already being studied as a potential treatment for metabolic dysfunction-associated steatohepatitis, a type of fatty liver disease. Researchers now believe the same hormone might also play a role in weight reduction.

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Lead author Matthew Potthoff, PhD, a professor of biochemistry and physiology at the OU College of Medicine and deputy director of the OU Health Harold Hamm Diabetes Center, said the hormone sends “signals” to the lower back region of 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,” Potthoff wrote.

“We thought we would find that it signaled to the hypothalamus, 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.”

Potthoff said the brain circuit responsible for these metabolic benefits appears to “mediate the effects of FGF21,” though that same mechanism may also be linked to side effects such as gastrointestinal problems and bone loss.

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“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,” he explained.

Researchers noted that while FGF21 and GLP-1 affect the same brain region, they operate in different ways. GLP-1 drugs reduce food intake by suppressing appetite, while FGF21 increases metabolic rate, enhancing the body’s energy-burning processes.

Potthoff expressed hope that future research could lead to an FGF21-based treatment that supports both weight loss and liver health, though he emphasized that additional studies will be needed to explore its potential.

Dr. Peter Balazs, a hormone and weight loss specialist in New York and New Jersey, said the study opens the door to new questions about how obesity might be addressed through metabolism rather than diet alone.

“However, this is a preclinical [mouse] study using diet-induced obesity models, which is not fully relevant or similar to human obesity’s chronic metabolic adaptations,” Balazs said.

Balazs pointed out that obese people already have higher levels of FGF21 circulating in their blood, making it uncertain whether adding more of the hormone would create the same effect seen in animals.

“There are also important clinical concerns, such as whether FGF21 analogs can cause side effects like digestive issues and bone loss, which is especially risky since obesity already increases the chance of fractures,” he cautioned.

Earlier human trials of FGF21 showed a weight loss range between 5% and 8%, Balazs said, which he described as “less impressive” compared to the average 15% seen with GLP-1 drugs.

He also noted that it remains unclear whether long-term use of FGF21 treatments could lead to tolerance, reducing their effectiveness over time.

“The study is a nice first step toward alternative biochemical pathways for treating obesity,” Balazs added.

“However, clinical adoption will require safety trials that include bone density monitoring, along with confirmatory data in humans.”