Researchers at McMaster University have identified an unexpected role for a naturally occurring hormone previously associated with appetite suppression and weight management. The study reveals that this hormone, known as GDF15, directly protects the liver from inflammation through a novel signaling pathway, offering potential new avenues for treating advanced liver disease regardless of weight loss.
The findings, published in Cell Metabolism on August 10, 2026, demonstrate that GDF15 can reduce liver inflammation and slow the progression of liver scarring even in the absence of weight loss. This discovery challenges the prevailing understanding that GDF15’s therapeutic effects are mainly linked to its influence on appetite and body weight.
A Promising Target for Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of fatty liver disease, affects millions globally and can progress to cirrhosis, liver cancer, or organ failure. While newer weight-loss medications have improved patient outcomes, residual liver inflammation often remains a concern even after significant weight reduction.
By elucidating a biological mechanism that regulates liver inflammation directly, the research opens the possibility of developing therapies that target inflammation alongside conventional strategies aimed at reducing body weight and hepatic fat content.
“These results confirm that GDF15 does far more than modulate appetite and body weight,” said Dr. Gregory Steinberg, professor in the Department of Medicine at McMaster University and co-director of the Centre for Metabolism, Obesity and Diabetes Research (MODR). “We found that GDF15 engages a brain-to-liver signaling axis that suppresses hepatic inflammation and mitigates fibrosis. This reshapes our perspective on the hormone and indicates it might form part of the body’s intrinsic defense system against chronic liver injury.”
Decoding the Brain-to-Liver Signal Pathway
To investigate how GDF15 influences advanced liver disease, researchers employed mouse models that closely mimic human MASH pathology. Using a combination of genetic manipulation, pharmacological interventions, genomic profiling, and spatial transcriptomics, the team analyzed the hormone’s downstream effects.
The investigation revealed that GDF15 triggers signaling originating in the brain, which propagates through the nervous system and culminates in the release of glucocorticoids—steroid hormones critical for metabolism, immune regulation, and stress response.
These glucocorticoids subsequently exert anti-inflammatory actions within the liver. Critically, the protective effects were observed independent of changes in food intake, body weight, or hepatic fat accumulation. Additionally, GDF15 was shown to decelerate the progression of liver fibrosis—the buildup of scar tissue associated with chronic liver disease.
“Thanks to advanced spatial technologies, we can now observe how GDF15 reprograms liver cells to dampen inflammation and fibrosis,” noted Dr. Dongdong Wang, first and corresponding author of the study and assistant professor in the Department of Medicine at McMaster University. “Rather than inducing harm, GDF15 appears to restore immune balance in the liver, shifting immune cells toward a protective phenotype that curtails inflammation and preserves tissue integrity.”
An Additional Dimension of GDF15 Function
In a 2023 study, Dr. Steinberg and Dr. Wang demonstrated that GDF15 plays a role in sustaining energy expenditure during weight loss. The current study introduces another dimension to its functionality—directly safeguarding liver health via an anti-inflammatory mechanism previously unrecognized.
Together, both studies underscore the multifaceted nature of GDF15 and may inform the design of targeted therapies aimed specifically at combating liver inflammation—a key driver of MASH progression that has historically posed treatment challenges.
Dr. Steinberg, who serves as an executive member of NexusHealth at McMaster, chief scientific officer, and shareholder and co-founder of Espervita Therapeutics, recently contributed to preclinical research outlining a promising compound for managing advanced liver disease.
While that earlier work explored a potential therapeutic agent, this latest study uncovers an endogenous pathway the body already employs to regulate liver inflammation. Understanding these natural processes could significantly enhance efforts to develop next-generation treatments for MASH and related conditions.
Integrating Weight Management With Anti-Inflammatory Strategies
“Existing treatment protocols primarily emphasize lowering body weight and reducing liver fat,” explained Dr. Steinberg. “However, our findings suggest that pairing such approaches with interventions targeting inflammation itself may yield superior results. By decoding the body’s native protective mechanisms, we aim to unlock novel therapeutic opportunities for patients suffering from MASH.”
The study involved collaboration with Rune E. Kuhre and Sebastian B. Jørgensen from Novo Nordisk A/S. Funding was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canadian Institutes of Health Research (CIHR), and Diabetes Canada. Novo Nordisk supported the research and supplied the GDF15 used in experimental procedures.