The cause and consequences of diet-induced anorexia during lung cancer cachexia

• Applicant: Stefan Kotschi
• Subject Area: Endocrinology, Diabetology, Metabolism ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563492699

Approximately 50-80% percent of all cancer patients undergo a phenomenon called cachexia, which is the unvoluntary weight loss that occurs independent of treatments such as chemotherapy. Despite its high prevalence and association with higher mortality, no approved treatments exist. Weight loss can be caused either by a reduction of food intake, a phenomenon known as anorexia, or an increase of energy expenditure. Both mechanisms can be observed in cancer cachexia. To therapeutically increase food intake, dietary interventions, particularly high-caloric diets, are being explored. However, clinical trials have shown limited success, as increasing caloric intake is not sufficient to combat cachexia, and patients will frequently continue to lose weight despite adequate nutritional intake. Food intake is mostly regulated by neural circuits in the brainstem and hypothalamus and previous research in the field has hinted at pathological activity in those areas during cachexia, but the specific mechanisms are unknown. One type of cancer in which cachexia is highly prevalent is lung adenocarcinoma. Our research group has utilized a genetically engineered mouse model to identify mutations that accelerate cachexia. Paradoxically, feeding those cachexia-prone mice a high-caloric, high-fat diet drastically reduced food intake and worsened cachexia. This proposal aims to uncover the mechanisms behind the reduction of food intake in this model of cachexia and the effects on metabolically active tissues such as skeletal muscle and adipose tissue. To achieve these aims, the following experiments are planned. To characterize the feeding behavior during cachexia, I will perform food preference tests to assess if cachectic animals have a specific aversion against high-fat diet, and pair feeding experiments, where the food intake of control animals is matched with cachectic animals. This will demonstrate what fraction of the weight loss is caused by anorexia. To study the mechanisms of anorexia in the brain, I will conduct state-of-the-art spatial transcriptomics on the brain stem, which will allow me to uncover specific neuronal populations whose activation causes cachexia. Next to anorexia, weight loss in cachexia has also been reported to be caused by increased metabolic activity in fat tissue, in particular brown adipose tissue, or skeletal muscle caused by the tumor. I will assess markers of wasting in tissues from cachectic animals to investigate direct effects of the tumor on those tissues. Finally, to test the influence of brown adipose tissue activation on cachexia in our model, I will house animals at thermoneutrality, at which brown fat is inactive, and measure the progression of cachexia. This research will shed light on the causes and consequences of high-fat diet induced anorexia in a model of lung cancer cachexia.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Thales Papagiannakopoulos, Ph.D.