Oxaliplatin triggers adipose and muscle wasting through cancer-independent metabolic and CNS pathways in mouse models.

Oxaliplatin, a platinum-based chemotherapeutic, is a first-line treatment for colorectal and other cancers frequently associated with cachexia. The extent to which oxaliplatin induces cachexia independently of cancer and the mechanisms involved remain unclear. Here we show that treatment with a human-equivalent dosage of oxaliplatin leads to cachexia-like symptoms in mice commonly observed in cancer patients, including severe loss of body mass resulting from adipose tissue depletion and wasting of skeletal muscle. The mice experience alterations in whole-body metabolism, including decreased food intake, reduced ambulatory activity, lowered core body temperature, and altered respiratory exchange ratio. Histological analyses demonstrate marked muscle fiber atrophy and increased immune cell infiltration. Transcriptomics analyses performed on subcutaneous adipose tissue, skeletal muscle, and the hypothalamus identify metabolic rewiring as a dominant response associated with chemotherapy-induced cachexia. RNA-seq demonstrates signaling pathways associated with these processes across muscle, adipose, and hypothalamus. Specifically, adipokine genes are dysregulated in white adipose tissue and in the hypothalamus, while genes involved in inflammatory pathways are upregulated in muscle.