A Weight-Loss Hormone May Protect the Liver Independently of Weight Loss, Study Finds

A hormone best known for suppressing appetite and promoting weight loss may also help protect the liver from inflammation and scarring, even without changes in body weight. New research from McMaster University suggests that GDF15 can act through a brain-to-liver signaling pathway, potentially revealing a new therapeutic target for advanced fatty liver disease.

Published in Cell Metabolism, the study found that GDF15 reduced liver inflammation and fibrosis in mouse models independently of its effects on food intake and liver fat. The findings suggest that the hormone’s influence on liver health may extend beyond the metabolic benefits associated with eating less and losing weight.

Why liver disease needs new options

Metabolic dysfunction-associated steatohepatitis, or MASH, is a progressive form of fatty liver disease characterized by excess liver fat, inflammation and liver-cell injury. In some people, it can lead to increasing fibrosis and eventually cirrhosis, liver cancer or liver failure.

Weight loss and newer metabolic treatments, including GLP-1-based therapies, can improve liver fat and other aspects of metabolic health. However, inflammation and fibrosis are distinct components of MASH and may not completely resolve alongside reductions in body weight or liver fat.

Researchers are therefore interested in treatments that could act more directly on the inflammatory and fibrotic processes involved in disease progression.

How GDF15 signals from brain to liver

To investigate GDF15’s role, the McMaster team used mouse models of MASH alongside genetic tools, pharmacological interventions, genomic analysis and spatial transcriptomics.

The researchers found evidence that GDF15 activates signaling in the brain that ultimately influences the liver. The pathway involves neural communication and glucocorticoids, steroid hormones that help regulate metabolism, immune responses and the body’s response to stress.

These signals altered inflammatory activity in the liver, including the behavior of local immune cells. Importantly, the protective effects were observed even under conditions where they could not simply be explained by reduced food intake, weight loss or major changes in liver fat.

GDF15 signaling was also associated with reduced fibrosis, the accumulation of scar tissue that accompanies chronic liver injury. Cellular analyses showed changes in liver and immune-cell states consistent with lower inflammatory and fibrotic activity.

The findings therefore suggest that GDF15 can influence liver pathology through a neuroendocrine mechanism rather than solely through its effects on appetite and body weight.

Broader implications for future therapies

The findings build on previous research from the McMaster group. In 2023, the researchers reported that GDF15 can help maintain energy expenditure during caloric restriction, potentially contributing to its effects on body-weight regulation.

The latest work points to another role for the hormone: influencing inflammation and fibrosis through communication between the brain and liver.

If a similar pathway operates in humans, it could eventually provide researchers with new targets for treating MASH. Future therapies might potentially combine approaches that improve metabolic health and reduce liver fat with mechanisms that more directly influence inflammation and fibrosis.

However, the current results do not show that GDF15 itself can treat MASH in people. The work remains preclinical, and mouse models cannot fully reproduce the complexity of human metabolic liver disease.

The involvement of glucocorticoids also requires careful interpretation. Although these hormones can suppress inflammatory responses, the finding does not mean that conventional glucocorticoid treatment would reproduce GDF15’s effects. Long-term or excessive glucocorticoid exposure can itself produce significant metabolic side effects.

Senior author Gregory Steinberg and colleagues suggest that understanding the signaling pathway could help identify therapeutic strategies aimed at the inflammatory and fibrotic components of MASH. Further research will be needed to determine which parts of the pathway could be targeted safely and effectively.

The study involved collaborators from Novo Nordisk and received support from Canadian research funding organizations and Diabetes Canada. Given the preclinical nature of the findings, independent studies and eventually human research will be important for determining their clinical significance.

For now, the research provides evidence that GDF15’s biological effects may extend beyond appetite suppression and weight regulation. By identifying a brain-to-liver pathway associated with reduced inflammation and fibrosis in experimental MASH, the study suggests a potential new direction for understanding — and eventually targeting — advanced metabolic liver disease.