Researchers Identify Mechanism for Body Weight-Reducing Hormone

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OKLAHOMA CITY – A hormone that reverses obesity in mice 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. The finding, from University of Oklahoma researchers, is published in Cell Reports.

The study provides valuable new insight into the naturally occurring hormone, called FGF21 (fibroblast growth factor 21), which is already involved in drug development. Drugs that target the pathway of this hormone are currently being examined in clinical trials for the treatment of MASH (metabolic dysfunction-associated steatohepatitis), a form of fatty liver disease.

Researcher Matthew Potthoff, Ph.D., is the lead author of the study, which demonstrates that the hormone produces its beneficial effects by signaling to the hindbrain, or 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,” 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.”

Specifically, FGF21 signals to a part of the hindbrain known as the nucleus of the solitary tract (NTS) and the area postrema (AP). The NTS and AP essentially make a “phone call” to a different brain region called the parabrachial nucleus, a signaling process that is necessary for FGF21 to exert its beneficial metabolic effects to reduce body weight.

“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 analogues have side effects like gastrointestinal issues and, in some cases, bone loss.”

Although they target the same area of the brain, FGF21 and GLP-1 act in different ways. GLP-1 works by reducing food intake, whereas FGF21 increases the metabolic rate, which burns energy and leads to weight loss.

Ultimately, Potthoff hopes to see a new drug for weight loss 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 analogues to reverse MASH,” he said.