Separating food intake-dependent and -independent effects in cancer cachexia

Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle tissues, with diminished food intake due to anorexia commonly cited as a cause. However, to what extent reduced food intake drives these symptoms and other cachexia phenotypes, such as fatigue, remains generally unclear in preclinical models and patient populations. Here we demonstrate the critical need to address this question in cancer cachexia research. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and wasting of fat and muscle, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing fatigue. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.