Plasma metabolomic changes in mice with time-restricted feeding-attenuated spontaneous metastasis of Lewis lung carcinoma

Authors: Yan, Lin; Rust, Bret; Picklo, Matthew

Submitted to: Anticancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2020
Publication Date: 4/1/2020
Citation: Yan, L., Rust, B.M., Picklo, M.J. 2020. Plasma metabolomic changes in mice with time-restricted feeding-attenuated spontaneous metastasis of Lewis lung carcinoma. Anticancer Research. https://doi.org/10.21873/anticanres.14137.
DOI: https://doi.org/10.21873/anticanres.14137

Interpretive Summary: Lifestyle changes in the modern world (for example, overeating during a “wrong time” of the day) are environmental cues that disrupt the internal biological clock controlling our physiological functions (for example, the eating/fasting pattern) and can contribute to obesity. Obesity, a risk factor for cancer, is associated with a poor prognosis and a greater risk of developing recurrent or metastatic cancer, which directly affects the survival and quality life of cancer patients. We investigated whether time-restricted feeding (TRF), restriction of food intake to the active phase of the day (the dark phase for rodents), altered plasma metabolic profiles in a mouse model of lung cancer. Feeding mice unrestrictedly an obesity-causing, high-fat diet enhanced tumor growth in the lungs and resulted in changes in plasma concentrations of metabolites related to protein, lipids, and carbohydrate metabolism. TRF of the same high-fat diet mitigated the high-fat diet-enhanced tumor growth and alleviated the high-fat diet-mediated alterations in plasma metabolites. This improvement may contribute to the TRF inhibition of tumor growth in the lungs. Findings from this study point to potential plasma fingerprints of TRF efficacy for reducing cancer growth and indicate that maintaining a healthy eating habit is beneficial in reducing the risk of obesity and associated diseases including cancer.

Technical Abstract: Erratic eating times disrupt diurnal rhythms of metabolism and may contribute to obesity. Time-restricted feeding (TRF) to the active phase of the day (the dark phase for nocturnal rodents) restores metabolic homeostasis in mice. With the goal of determining potential fingerprints underlying TRF efficacy, we performed untargeted metabolomic analysis on plasma from a study demonstrating that TRF (12 hours, dark phase) attenuates obesogenic diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC). We identified 152 compounds, of which 24 differed among the four dietary groups (non-LLC-bearing mice fed the standard AIN93G diet and LLC-bearing mice fed the AIN93G, the high-fat diet (HFD), or TRF of the HFD). Component 1 of sparse partial least squares–discriminant analysis showed a clear separation between non-LLC-bearing mice and LLC-bearing mice. TRF shifted the metabolic profile of LLC-bearing mice closer to that of non-LLC-bearing mice. Major metabolites responsible for the changes were elevations of alpha-tocopherol, docosahexaenoic acid, cholesterol, dihydrocholestrol, isoleucine, leucine, and phenylalanine and decreases of lactic acid and pyruvic acid in LLC-bearing mice particularly those fed the HFD. TRF reduced the aforementioned elevations, but it did not alter lactic acid, lactamide, and pyruvic acid. The study showed that TRF, through its temporal regulation of food intake to a fixed time of the day, shifted the metabolic profile of LLC-bearing mice towards that of non-LLC-bearing controls. This improvement in metabolism may have contributed to TRF mitigation of LLC metastasis.