Appetite-linked GDF15 hormone found to protect the liver from inflammation

Researchers have identified a previously unknown pathway through which growth differentiation factor 15 – a hormone best known for suppressing appetite – helps to protect the liver against inflammation and scarring, independently of weight loss

A research teams at McMaster University, Hamilton, Ontario, Canada, has discovered that a naturally occurring hormone that is best known for its role in suppressing appetite and promoting weight loss can also help to protect the liver from inflammation, via a previously unknown signalling pathway. The finding opens up novel avenues for the treatment of fatty liver disease.

The findings revealed that growth differentiation factor 15 (GDF15) suppressed liver inflammation and slowed the progression of liver scarring independently of weight loss – a surprising discovery that challenged longstanding assumptions about how the hormone functions.

Millions of people worldwide live with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease that can progress to cirrhosis, liver cancer, and liver failure. Although novel weight-loss medications have improved outcomes for many patients, liver inflammation often persists even after significant weight loss. This research has identified a biological pathway that helps to regulate liver inflammation, suggesting that future treatments may be able to complement existing weight-loss therapies.

“Our findings show that GDF15 does much more than regulate appetite and body weight,” said Dr. Gregory Steinberg, senior author of the study and a professor in McMaster University’s department of medicine, as well as serving as co-director of the university’s Centre for Metabolism, Obesity and Diabetes Research.

“We discovered that GDF15 activates a natural brain-to-liver signalling pathway that helps suppress liver inflammation and reduce fibrosis. This changes how we think about the hormone and suggests it may be part of the body’s own defence system against chronic liver injury,” he said.

The researchers combined genetic, pharmacological, genomic and spatial transcriptomic approaches to investigate the role of GDF15 in advanced liver disease and used mouse models that closely mimic human MASH. They found that GDF15 activated a signalling pathway running from the brain to the nervous system which led to the release of glucocorticoids – a class of steroid hormone that plays a vital role in metabolism, immune function and the stress response.

These glucocorticoids dampened inflammation in the liver, and the protective effects occurred independently of any changes in food intake, body weight or liver fat. GDF15 was also found to limit the progression of liver fibrosis, a build-up of scar tissue associated with advanced disease.

“GDF15 helps reprogramme liver cells to reduce inflammation and scarring by advanced spatial technology,” said Dr. Dongdong Wang, first and corresponding author of the study and assistant professor in McMaster’s department of medicine.

“It appears to help calm the liver’s immune system … [and] shifts immune cells into a more protective and less active state, helping to reduce inflammation and prevent damage to the liver,” he added.

Research published in 2023 by Steinberg and Wang showed that GDF15 helps to maintain calorie burning during weight loss but this study revealed an entirely different role for the hormone showing it to protect the liver through a previously unknown anti-inflammatory pathway. Together, the researchers say, the two studies could help to guide the development of future therapies aimed specifically at liver inflammation, a major driver of disease progression that remains difficult to treat.

Steinberg, an executive member of NexusHealth at McMaster and chief scientific officer, shareholder, and co-founder of Espervita Therapeutics, recently co-authored preclinical research that described a promising drug candidate for advanced liver disease. While that work focused on a potential therapeutic compound, this study identifies a biological pathway that the body naturally uses to suppress liver inflammation and offers insight that could inform the next generation of treatments.

“Current therapies largely focus on reducing body weight and liver fat,” said Steinberg.

“Our work suggests there may be value in combining those approaches with therapies that directly target inflammation. By understanding how the body naturally protects the liver, we can identify new opportunities to develop more effective treatments for people living with MASH.”

For further reading please visit: 10.1016/j.cmet.2026.07.008