Researchers at McMaster University have discovered that a naturally occurring hormone best known for suppressing appetite and promoting weight loss also helps protect the liver from inflammation through a previously unknown signalling pathway, opening new possibilities for treating advanced fatty liver disease.
The findings, published in Cell Metabolism on Aug. 10, reveal that the hormone GDF15 can suppress liver inflammation and slow the progression of liver scarring independently of weight loss — a surprising discovery that challenges longstanding assumptions about how the hormone works.
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.
While new weight-loss medications have improved outcomes for many patients, liver inflammation often persists even after significant weight loss. The new research identifies a biological pathway that helps regulate liver inflammation, suggesting 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,” says senior author Gregory Steinberg, professor in the Department of Medicine and co-director of the Centre for Metabolism, Obesity and Diabetes Research (MODR).
“We discovered that GDF15 activates a natural brain-to-liver signaling 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 defense system against chronic liver injury.”
Using mouse models that closely mimic human MASH, researchers combined genetic, pharmacological, genomic and spatial transcriptomics approaches to investigate the role of GDF15 in advanced liver disease. They found that GDF15 activates signalling from the brain to the nervous system that leads to the release of glucocorticoids, a class of steroid hormones that play a vital role in metabolism, immune function, and the stress response.
The glucocorticoids help dampen inflammation in the liver and those protective effects occur independently of changes in food intake, body weight or liver fat. GDF15 was also found to help limit the progression of liver fibrosis, a buildup of scar tissue associated with advanced disease.
“GDF15 helps reprogram liver cells to reduce inflammation and scarring by advanced spatial technology,” says Dongdong Wang, first and corresponding author of the study and assistant professor McMaster’s Department of Medicine.
“Instead of causing liver damage, GDF15 appears to help calm the liver’s immune system. It shifts immune cells into a more protective and less active state, helping reduce inflammation and prevent damage to the liver.”
Research published in 2023 from Steinberg and Wang showed that GDF15 helps maintain calorie burning during weight loss, but the new study reveals an entirely different role for the hormone: protecting the liver through a previously unknown anti-inflammatory pathway.
Together, researchers say the two studies could help 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 describing a promising drug candidate for advanced liver disease. While that work focused on a potential therapeutic compound, the new study identifies a biological pathway the body naturally uses to suppress liver inflammation, offering new insight that could inform the next generation of treatments.
“Current therapies largely focus on reducing body weight and liver fat,” says 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.”
In addition to McMaster researchers, collaborators included Rune E. Kuhre and Sebastian B. Jørgensen of Novo Nordisk A/S. The research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. Novo Nordisk provided research support and supplied the GDF15 hormone used in the study.