Cold Exposure Suppresses Tumor Growth through BAT Activation

Glucose uptake is critical for cancer glycolysis, and activation of brown adipose tissue (BAT), which can occur through cold, diet, or drugs, supports uptake of glucose in adipocytes. However, despite the speculation that BAT activation could be a potential target to treat other diseases like type 2 diabetes, the role that BAT activation plays in tumor growth remains undetermined. Seki, Yang, and colleagues, using cold acclimatization, showed that colorectal cancer (CRC) tumor growth was reduced by approximately 80% at 4°C as compared to 30°C. Evaluation of the alterations to the tumor microenvironment (TME) at high versus low temperatures revealed inhibition of hypoxia and angiogenesis, a reduction in the CD45⁺ myeloid cell population, and increased survival of tumor-bearing mice under cold exposure, with these findings also being shown in other tumor types. Tumor-bearing mice also demonstrated BAT activation as indicated by an increase in the levels of UCP1, a key thermogenic protein, as well as a reduction in BAT glucose uptake after cold exposure. Moreover, the metabolism of CRC tumor–bearing mice at 4°C was increased, with these mice also demonstrating reduced fasting blood glucose levels and improved insulin sensitivity. Conversely, removal of BAT, feeding mice a high (15%) glucose diet, or deletion of Ucp1 reversed the tumor-suppressive phenotype observed after cold exposure, suggesting that BAT is primarily responsible for cold-triggered tumor suppression. Additionally, glycolysis, key glycolytic enzymes, glucose transporter (GLUT) expression—especially Glut1, as well as PI3K, AKT, and mTOR expression were inhibited in tumors undergoing cold exposure but were increased in the BAT of these mice, suggesting that glycolysis is suppressed in tumors after cold exposure. Further analyses demonstrated that cold exposure leads to BAT activation and reduced glucose uptake in human cancers as well. In conclusion, this study shows that activation of thermogenic metabolism in BAT through cold exposure can reduce tumor growth and suggests this process as a potential therapeutic approach for multiple tumor types.

Seki T, Yang Y, Sun X, Lim S, Xie S, Guo Z, et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 2022;608:421–8.

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