Decreased food intake contributes to elevated insulin-responsiveness in pre-clinical cancer cachexia

PurposeCancer cachexia is a life-threatening complication of advanced malignancies, driven by anorexia and profound systemic metabolic reprogramming. Insulin action in skeletal muscle is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between reduced nutrient intake and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies. MethodsWe assessed metabolic rewiring by glucose tolerance test and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as mice towards C26 cachectic mice. ResultsCachectic C26-tumor-bearing mice displayed reduced body weight, lean, and fat mass, and food intake (-20%, -15%, -75%, -40%, respectively). Cachectic C26- and KPC-tumor mice showed improved glucose tolerance compared to non-cachectic mice, correlating inversely with tumor size. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice compared to non-cachectic and control mice. This increase was associated with enhanced AKT signaling. This was phenocopied in pair-fed non-tumor-bearing mice to match the food intake of cachectic mice, where glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling were all enhanced by food restriction. ConclusionsOur findings suggest that enhanced skeletal muscle insulin responsiveness in cachectic tumor-bearing mice is due to anorexia-induced adaptations, highlighting AKT signaling as a key node connecting nutrient status to muscle glucose metabolism in cancer cachexia. HighlightsO_LIC26 and KPC cancer-induced weight loss (cachexia) increases glucose tolerance in mice C_LIO_LIInsulin responsiveness is increased in cachectic, but not in non-cachectic, tumor-bearing mice. C_LIO_LILowered food intake drives elevated muscle insulin responsiveness in cachectic mice C_LI