A hormone already known for suppressing appetite and enabling drugs like semaglutide may have a second job: shielding the liver from inflammation and scarring, according to a new study published in the journal Cell Metabolism by researchers at McMaster University.
The hormone, GDF15, is best known for its role in reducing food intake and body weight -- it is part of the biological pathway that newer weight-loss and diabetes drugs are designed to mimic or amplify. But in mice bred to develop metabolic dysfunction-associated steatohepatitis, or MASH, an advanced and increasingly common form of fatty liver disease, the McMaster team found GDF15 suppressed liver inflammation and slowed the buildup of scar tissue even when it produced no change in the animals' food intake, body weight, or liver fat.
Using genetic, pharmacological and spatial transcriptomics techniques, the researchers traced the effect to a newly described brain-to-liver signaling pathway. GDF15 triggers the release of glucocorticoids, steroid hormones involved in metabolism, immune regulation and the stress response, which in turn reprogram immune cells in the liver toward a less inflammatory state and blunt the progression of fibrosis, the scarring associated with advanced liver disease.
GDF15 does much more than regulate appetite and body weight. We discovered that it activates a natural brain-to-liver signaling pathway that helps suppress liver inflammation and reduce fibrosis.
Gregory Steinberg, professor of medicine and co-director of the Centre for Metabolism, Obesity and Diabetes Research, McMaster University
MASH, formerly known as NASH, affects an estimated hundreds of millions of people worldwide and can progress to cirrhosis, liver cancer or liver failure. Most existing GDF15-related therapies, including the appetite-suppressing pathway exploited by GLP-1 drugs, have been developed with weight loss as the primary target rather than liver protection specifically.
The McMaster findings suggest the two effects, appetite suppression and liver protection, may be separable, raising the possibility of therapies that target liver inflammation directly, independent of whether a patient loses weight. That could matter for patients who do not respond well to weight loss alone, or whose liver damage has progressed regardless of weight changes.
The research so far has been conducted only in mouse models engineered to mimic the human disease, and the authors caution that human studies will be needed to confirm whether the same brain-to-liver pathway is active, and therapeutically useful, in people. The team says it now plans to investigate whether existing GDF15-based drugs already in development can be adjusted to more directly engage the liver-protective pathway.
