Hidden GDF15 Pathway May Protect the Liver Independent of Weight Loss

A hormone best known for curbing appetite and aiding weight loss may also protect the liver from damaging inflammation, McMaster University researchers in Canada have found. The team found GDF15 works through a previously unknown signaling pathway that reduces liver inflammation and slows the buildup of scar tissue even without weight loss, challenging the idea that the hormone's benefits come mainly from its effect on appetite and body weight. The findings, published in Cell Metabolism, point to a new approach to metabolic dysfunction-associated steatohepatitis (MASH), a liver disease that affects millions worldwide and can progress to cirrhosis, liver cancer and liver failure.

Studying mouse models designed to closely resemble human MASH, the researchers combined genetic, pharmacological, genomic and spatial transcriptomics methods to trace how GDF15 acts. They found the hormone triggers brain-to-nervous-system signaling that releases glucocorticoids, steroid hormones involved in metabolism, immune function and the stress response. These hormones reduced liver inflammation independently of food intake, body weight or liver fat, and also slowed liver fibrosis, the buildup of scar tissue that accompanies advanced disease.

"Our findings show that GDF15 does much more than regulate appetite and body weight," said Gregory Steinberg, a professor in McMaster's Department of Medicine and co-director of its Center for Metabolism, Obesity and Diabetes Research, and senior author of the study. "We discovered that GDF15 activates a natural brain-to-liver signaling pathway that helps suppress liver inflammation and reduce fibrosis." Dongdong Wang, the study's first and corresponding author, said the hormone appears to shift immune cells in the liver into "a more protective and less active state."

The result builds on a 2023 study by the same team, which found that GDF15 helps sustain calorie burning during weight loss. Current MASH therapies largely focus on reducing body weight and liver fat, Steinberg said, and the new pathway raises the possibility of combining those approaches with therapies that directly target liver inflammation.