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

Author

Listed:
  • Takahiro Seki

    (Karolinska Institutet)

  • Yunlong Yang

    (Karolinska Institutet
    Fudan University)

  • Xiaoting Sun

    (Karolinska Institutet
    Wenzhou Medical University)

  • Sharon Lim

    (Karolinska Institutet)

  • Sisi Xie

    (Fudan University
    Longyan First Hospital Affiliated to Fujian Medical 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
    People’s Hospital of Hangzhou Medical College)

  • 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)

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.

Suggested Citation

  • 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 & Y, 2022. "Brown-fat-mediated tumour suppression by cold-altered global metabolism," Nature, Nature, vol. 608(7922), pages 421-428, August.
  • Handle: RePEc:nat:nature:v:608:y:2022:i:7922:d:10.1038_s41586-022-05030-3
    DOI: 10.1038/s41586-022-05030-3
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    Cited by:

    1. Jinhong Xu & Le Cui & Jiaqi Wang & Shasha Zheng & Huahua Zhang & Shuo Ke & Xiaoqin Cao & Yanteng Shi & Jing Li & Ke Zen & Antonio Vidal-Puig & Chen-Yu Zhang & Liang Li & Xiaohong Jiang, 2023. "Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Vincent de Laat & Halit Topal & Xander Spotbeen & Ali Talebi & Jonas Dehairs & Jakub Idkowiak & Frank Vanderhoydonc & Tessa Ostyn & Peihua Zhao & Maarten Jacquemyn & Michele Wölk & Anna Sablina & Koen, 2024. "Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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