High-fat, low-carb diet reduces tumor growth and induces liver metabolism remodeling in a breast cancer mouse model

Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-week-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 weeks. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR and Western Blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of pro-tumorigenic factors ( Ang2, Hgf, Mki67). Moreover, a decrease of metabolic enzymes ( Pfk, Bdh1, Scot1) highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of Pepck, Foxo1, and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.