The Silenced Clock Gene
In cachexia, liver metabolism is fundamentally reprogrammed. One gene, which normally regulates the liver's activity throughout the day, ceases to function properly. Using a mouse model, the researchers discovered that this "internal clock" was almost completely shut down. "After reactivating the gene, known as REV-ERBα, specifically in the liver of affected mice, the loss of body mass was significantly reduced," says Dr. Doris Kaltenecker, co-first author of the study alongside Dr. Søren Fisker Schmidt, and researcher at the Institute for Diabetes and Cancer at Helmholtz Munich.
Liver-Derived Signaling Molecules Drive Cachexia
The team showed that REV-ERBα regulates several genes involved in the production of liver-derived signaling molecules. When this clock gene is inactive, the liver releases increased levels of factors that promote disease progression. Three of these so-called hepatokines (LBP, ITIH3, and IGFBP1) are central to the newly discovered mechanism. In cell culture experiments, they triggered catabolic, that is tissue-degrading, processes in muscle and fat cells, which are precisely the processes responsible for the physical wasting seen in cachexia. In addition, the levels of these proteins were markedly elevated in the blood of cachectic patients with various types of cancer. In preclinical models, targeted inhibition of these factors successfully mitigated their harmful effects.
Perspectives for Diagnosis and Therapy
"For the first time, we were able to show that the liver is not merely a passive responder to cachexia, but actively contributes to the progression of the disease," says Dr. Mauricio Berriel Diaz, who led the study at Helmholtz Munich. "Our findings open up new possibilities to better diagnose the syndrome and explore therapeutic interventions." The study also provides a comprehensive data resource on the role of the liver in cachexia – ranging from molecular networks to cell type-specific changes and functional outcomes in preclinical models. This dataset is now available to the scientific community and can be used well beyond the model system studied.
In the long term, the identified factors could serve as biomarkers for cachexia risk or as targets for new therapies. "Given that there is currently no approved treatment for cachexia, we urgently need new approaches," emphasizes Prof. Stephan Herzig, Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Cancer at Helmholtz Munich, and Professor at the Technical University of Munich. "These results clearly demonstrate the importance of systemic organ interactions in the progression of cancer."
About the Researchers
Dr. Doris Kaltenecker is a scientist at the Institute for Diabetes and Cancer (IDC) at Helmholtz Munich, at the Joint Heidelberg-IDC Translational Diabetes Program of Heidelberg University Hospital, and at the German Center for Diabetes Research (DZD).
Dr. Mauricio Berriel Diaz is Deputy Director of the Institute for Diabetes and Cancer (IDC) at Helmholtz Munich, and a scientist at the Joint Heidelberg-IDC Translational Diabetes Program of Heidelberg University Hospital and the German Center for Diabetes Research (DZD).
Prof. Stephan Herzig is Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Cancer at Helmholtz Munich, and holds the Chair of Molecular Metabolic Control at the Technical University of Munich (TUM). He is also affiliated with the Joint Heidelberg-IDC Translational Diabetes Program of Heidelberg University Hospital and the German Center for Diabetes Research (DZD).
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has around 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
