According to researchers at McMaster University, the naturally occurring hormone GDF15 protects the liver from inflammation and slows the progression of scarring through a brain-to-liver signaling pathway independent of weight loss. Published in Cell Metabolism, the findings challenge longstanding assumptions about the hormone, which is best known for suppressing appetite and promoting weight loss.
Understanding GDF15 and Liver Disease Progression
Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease that can advance to liver failure, liver cancer, and cirrhosis, affects millions of people across the globe. Even though recent weight-loss drugs have bettered results for numerous patients, liver inflammation frequently remains even after substantial weight loss. The study uncovers a biological mechanism that helps control liver inflammation, pointing to the possibility that future treatments could work alongside current weight-loss medications, as noted by Gregory Steinberg, co-director of the Centre for Metabolism, Obesity and Diabetes Research (MODR) and professor in the Department of Medicine at McMaster University.
“Our findings show that GDF15 does much more than regulate appetite and body weight,” Steinberg stated according to the study. “We discovered that GDF15 activates a natural brain-to-liver signaling pathway that helps suppress liver inflammation and reduce fibrosis.”
Did you know? GDF15 was shown in previous 2023 research from Steinberg and Wang to help maintain calorie burning during weight loss, but this newer study reveals an entirely separate anti-inflammatory role.
How the Brain-to-Liver Signaling Pathway Operates
To explore GDF15’s part in advanced liver disease, investigators deployed mouse models closely resembling human MASH by merging genomic, spatial transcriptomics, pharmacological, and genetic methods. According to the study, GDF15 activates signaling from the brain to the nervous system that leads to the release of glucocorticoids, a class of steroid hormones vital to metabolism, immune function, and the stress response. These glucocorticoids help dampen inflammation in the liver independently of changes in food intake, body weight, or liver fat, while also limiting the progression of liver fibrosis.
“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 in McMaster’s Department of Medicine. “Instead of causing liver damage, GDF15 appears to help calm the liver’s immune system.”
Implications for Future MASH Treatments
Recently, Steinberg—who serves as an executive member of NexusHealth at McMaster alongside being a shareholder, co-founder, and chief scientific officer of Espervita Therapeutics—co-authored preclinical work outlining a promising drug candidate targeting advanced liver disease. While that project centered on a potential therapeutic molecule, the new research pinpoints a biological pathway naturally employed by the body to curb liver inflammation.
“Current therapies largely focus on reducing body weight and liver fat,” Steinberg notes. “Our work suggests there may be value in combining those approaches with therapies that directly target inflammation.” Collaborators on the study included Rune E. Kuhre and Sebastian B. Jørgensen of Novo Nordisk A/S, with research support and GDF15 hormone supplied by Novo Nordisk.
Frequently Asked Questions
What is GDF15?
GDF15 is a naturally occurring hormone best known for suppressing appetite and promoting weight loss. Recent research shows it also protects the liver from inflammation through a neuroendocrine pathway.
What is MASH?
Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of fatty liver disease that can progress to cirrhosis, liver cancer, and liver failure.
Does GDF15 require weight loss to protect the liver?
No. According to the McMaster University study, GDF15 suppresses liver inflammation and slows scarring independently of changes in body weight, food intake, or liver fat.