Brown-fat-mediated tumour suppression by cold-altered global metabolism

Takahiro Seki, Yunlong Yang, Xiaoting Sun, Sharon Lim, Sisi Xie, Ziheng Guo, Wenjing Xiong, Masashi Kuroda, Hiroshi Sakaue, Kayoko Hosaka, Xu Jing, Masahito Yoshihara, Lili Qu, Xin Li, Yuguo Chen and Yihai Cao ()
Additional contact information
Takahiro Seki: Karolinska Institutet
Yunlong Yang: Karolinska Institutet
Xiaoting Sun: Karolinska Institutet
Sharon Lim: Karolinska Institutet
Sisi Xie: Fudan University
Ziheng Guo: West China Hospital, Sichuan University
Wenjing Xiong: Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University
Masashi Kuroda: Tokushima University Graduate School
Hiroshi Sakaue: Tokushima University Graduate School
Kayoko Hosaka: Karolinska Institutet
Xu Jing: Karolinska Institutet
Masahito Yoshihara: Karolinska Institutet
Lili Qu: Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University
Xin Li: Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University
Yuguo Chen: Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University
Yihai Cao: Karolinska Institutet

Nature, 2022, vol. 608, issue 7922, 421-428

Abstract: Abstract Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1–6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

Date: 2022
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DOI: 10.1038/s41586-022-05030-3

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