Time-restricted feeding attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice

Authors: Yan, Lin; Sundaram, Sneha; Mehus, Aaron; Picklo, Matthew

Submitted to: Anticancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2019
Publication Date: 3/8/2019
Citation: Yan, L., Sundaram, S., Mehus, A.A., Picklo, M.J. 2019. Time-restricted feeding attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Anticancer Research. https://doi.org/10.21873/anticanres.13280.
DOI: https://doi.org/10.21873/anticanres.13280

Interpretive Summary: More than one third of the US adults are obese or overweight. In addition to excessive food intake and lack of physical activity, overeating during a “wrong” time of the day may play a major role in development of obesity by disturbing the daily rhythm of energy metabolism and balance between energy utilization and storage. Being obese at the time of cancer diagnosis is associated with poor prognosis and greater risk of developing recurrent or metastatic cancer, which directly affects the quality life and survival of cancer patients. We investigated whether restriction of food intake to the active phase of the day (12 hours per day) affected cancer spread in a mouse model of lung metastasis. We found that unrestricted feeding mice an obesity-causing, high-fat diet increased fat body mass and enhanced metastasis in the lungs. Restricted feeding of the same high-fat diet to the active phase did not reduce energy intake but lowered fat body mass compared to the unrestricted feeding. Furthermore, restricted feeding reduced the development and growth of metastases in the lungs and concentrations of cancer-promoting hormones in blood compared to the unrestricted feeding. Our findings indicate that eating during the active phase of the day reduces the body fat buildup and prevents the obesity-enhanced cancer spread in mice. It indicates that maintaining a healthy eating habit is beneficial in reducing the risk of obesity and associated diseases including cancer.

Technical Abstract: Obesity is a risk factor for cancer with demonstrated enhancement in malignant progression. Recent studies demonstrate that disruption of the daily feeding and fasting rhythm can contribute to the development of obesity. The hypothesis of this study was that time-restricted feeding (TRF) attenuates obesity-enhanced metastasis. In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were fed the standard AIN93G diet or a modified, obesogenic AIN93G diet containing 45% of energy from soybean oil (HFD) with or without dark phase restricted feeding (12 hours per day) for 10 weeks. Pulmonary metastases from a primary tumor, established by subcutaneous injection of LLC cells, were quantified. The percentage body fat of the TRF group was lower than that of the HFD group and was similar to that of the AIN93G group. The number and size of lung metastases were greater in the HFD group than in the AIN93G group but did not differ between the TRF and AIN93G groups. TRF prevented HFD-induced increases in plasma concentrations of glucose, insulin, proinflammatory cytokines (leptin, monocyte chemotactic protein-1, and plasminogen activator inhibitor-1), and angiogenic factors (angiopoietin-2, hepatic growth factor, and vascular endothelial growth factor). In conclusion, TRF attenuates the HFD-enhanced spontaneous metastasis of LLC. This protection may be through entrainment of circadian Clocks and metabolic regulators to the fixed feeding time that results in reductions in body adiposity and associated cancer-promoting inflammatory and angiogenic factors.