A hormone already famous for suppressing appetite and aiding weight loss has been found to have a surprising second role: directly protecting the liver from inflammation through a previously unknown brain-to-liver signaling pathway.

Researchers at McMaster University in Hamilton, Ontario, discovered that GDF15 (growth differentiation factor 15) activates a neural signaling route that triggers the release of glucocorticoids, which then suppress liver inflammation and slow the progression of fibrosis — all independently of any change in body weight or liver fat.

The findings, published in Cell Metabolism, challenge the long-held assumption that GDF15's health benefits stem solely from its appetite-suppressing effects.

Millions worldwide suffer from metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of fatty liver disease that can progress to cirrhosis, liver cancer, and liver failure. While new weight-loss drugs have improved outcomes for many patients, liver inflammation can persist even after significant weight loss, leaving a therapeutic gap.

Our findings show that GDF15 does much more than regulate appetite and body weight, said Professor Gregory Steinberg, co-director of McMaster's Centre for Metabolism, Obesity and Diabetes Research. We discovered that GDF15 activates a natural brain-to-liver signaling pathway that helps suppress liver inflammation and reduce fibrosis.

Using mouse models of advanced MASH, the team combined genetic, pharmacological, genomic, and spatial transcriptomics approaches to trace how GDF15 works. They found the hormone initiates signaling from the brain through the nervous system, ultimately causing glucocorticoid release. These steroid hormones then reprogram liver immune cells into a calmer, less inflammatory state.

The protective effects held regardless of food intake, body weight, or liver fat levels. GDF15 also slowed the accumulation of scar tissue that marks disease progression.

Combined with a 2023 finding that GDF15 helps maintain calorie burning during weight loss, the new results paint a picture of a hormone with dual therapeutic potential: reducing appetite while simultaneously shielding the liver from immune damage.

The work was funded by NSERC, CIHR, and Diabetes Canada, with additional support from Novo Nordisk.

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