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-wk-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 wk. 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 protumorigenic factors (Ang2, Hgf, and Mki67). Moreover, a decrease of metabolic enzymes (Pfk, Bdh1, and 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.NEW & NOTEWORTHY We demonstrate that carbohydrate restriction alone slows breast tumor growth by limiting glucose availability and exposing the metabolic inflexibility of cancer cells. Despite an antitumor effect, carbohydrate restriction also triggers a robust hepatic compensatory response that increases endogenous glucose production. These findings provide important new insights for the design of metabolic interventions in oncology, highlighting the central role of liver-tumor metabolic cross talk and showing that dietary strategies should consider whole body glucose homeostasis.