Scientists have uncovered a second role for a long established appetite suppressor, aiding weight loss. Researchers at McMaster University have discovered a previously unknown signaling pathway by which the hormone GDF15 can protect the liver from inflammation and prevent the progression of cirrhosis without any weight loss. The findings, published in Cell metabolism, break previous understanding and offer a bright, new potential treatment avenue for progressive fatty liver disease. Metabolic dysfuntion-associated steatohepatitis (MASH) affects millions of people both here in the United States and across the globe.
This disease involves the build up of fat in the liver, inflammation, and the progression of fibrosed tissue. In the absence of treatment this disease will only further progress into cirrhosis, end-stage liver disease, or cancer. It was historically thought that losing weight was the best treatment because this would theoretically shed the excess fat in the liver.
But, even after successful weight loss many patients still exhibit inflammation and fibrosis. It was the response to this residual damage that inspired this new research. Though, using mouse models of the human disease MASH that accurately ( by definition) reflects the metabolic state of the disease. By knocking out GDF15 itself or its receptor GFRAL they found it worsened inflammation and fibrosis in the liver without altering hepatic steatosis or insulin resistance. Administration of recombinant GDF15 was able to correct inflammation and fibrosis better than calorie restriction alone, ( in which food intake, body weight and hepatic steatosis were all decreased to the same extent). The effect was obviously not weight loss dependent.
Instead the hormone elicits a brain-to-liver circuit. GDF15 engages GFRAL receptors in the brainstem and triggers the hypothalamic-pituitary-adrenal axis. The body releases glucocorticoidsthat is, the same class of steroid hormones involved in the body’s stress response. When the hormones arrive in the liver they switch on glucocorticoid receptors within the cells of the liver and quietly reprogram the local immune system.
Inflammatory macrophages and certain B cells decrease, activated stellate cells that produce scar tissue become less active, and immune programs that support regeneration gain strength. Advanced spatial mapping of the tissue revealed the shift from an aggressive, destructive state to a more tranquil, regenerative one. “We found that GDF15 triggers an innate brain-to-liver communication pathway that acts to decrease liver inflammation and fibrosis, ” explained the researchers.
“This alters our conception of the hormone and indicates that it might be part of the body’s own defense mechanism against chronic liver injury.” First author Dongdong Wang stated that the hormone relaxes the immune system of the liver instead of harming it. It does so, by moving the cells into a less active and more protective mode. This is important because our therapies for advanced fatty liver are few at present. Patients find it difficult to lose or maintain their weight, and drugs to treat the disease have not yet been able to control the inflammatory and fibrotic aspects. The knowledge that GDF15 can operate through this subordinate neuroendocrine pathway opens the door for future treatments that can be tailored for this mechanism, on top of diet, lifestyle changes, or medications for people with persistent liver damage despite weight loss.