The Effects of Time-Restricted Feeding on Early Phases of Liver and Colon Carcinogenesis

The influence of dietary factors on carcinogenesis, particularly the role of high-fat diets, is well-documented, with such diets contributing to altered lipid metabolism, the development of metabolic stress, and chronic inflammation. Given the growing interest in time-restricted feeding (TRF) as a non-pharmacological intervention to improve metabolic health and prevent chronic diseases, this study was designed to investigate whether TRF has an effect on the development in well-characterized models of liver and colon carcinogenesis in rats. Previous research has suggested that TRF improves metabolic parameters such as glucose regulation, lipid profiles, and inflammatory markers, potentially reducing cancer risk. However, there remains limited information on the efficacy of TRF directly in the early-stage carcinogenesis, especially in the context of obesogenic dietary conditions. In our study, we utilized established experimental systems to induce carcinogenesis in male and female rats. For liver carcinogenesis, diethyl nitrosamine (DENA) was administered as a single dose to initiate tumor development. For colon carcinogenesis, azoxymethane (AOM) was administered in 2 doses for two consecutive weeks to initiate the process. Following the carcinogen administration, rats were assigned to either a high-fat diet (HFD) or a low-fat diet (LFD), and then further subdivided into two feeding regimens: ad libitum feeding (AdL) or TRF, where food access was restricted to an 8-hour window between 8 AM and 4 PM. The animals were sacrificed at either 6 or 12 months after carcinogen exposure to assess the impact of TRF on the development and progression of preneoplastic lesions in both the liver and colon under the influence of a high-fat diet. Our findings indicate that TRF does not significantly affect the development of early preneoplastic lesions in the liver or colon, regardless of dietary fat content. Specifically, no differences were observed between TRF and AdL groups in the size, distribution, or incidence of glutathione S-transferase placental form (GSTP)-positive lesions in the liver or aberrant crypt foci in the colon. Furthermore, TRF did not mitigate hepatic steatosis, a suspected driver of liver carcinogenesis in high-fat diet conditions, highlighting the persistence of metabolic dysfunction despite meal timing interventions. These results suggest that the protective effects of TRF in cancer prevention may be context-dependent and insufficient to counteract the effect of a high-fat diet during early carcinogenesis. The obesogenic environment induced by sustained high dietary fat intake likely overrides the metabolic benefits of TRF, exacerbating hepatic fat accumulation, insulin resistance, and inflammation—key drivers of preneoplastic lesion development. Our findings emphasize the limited efficacy of TRF in isolation as a strategy that can be applicable against diet-related cancers under obesogenic conditions. However, combining TRF with dietary modifications, such as reduced fat intake or lower caloric load, may amplify its benefits. Additionally, longer-term studies are needed to assess whether TRF can delay the progression of preneoplastic lesions to malignancy, rather than their initial development. In conclusion, while TRF offers metabolic advantages, its application requires integration with dietary quality improvements. These findings highlight the need for comprehensive dietary strategies that address both feeding patterns and nutritional content to effectively reduce cancer risk in populations affected by obesity and poor dietary habits.