棕色脂肪通过寒冷改变的全身代谢来抑制肿瘤

2022-08-18 10:49

我们预计，通过任何其他方法，如单独或与其他抗癌疗法相结合的药物和设备，冷暴露和激活BAT，将为有效治疗各种癌症提供一种通用方法。

SCI

17 August 2022

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

（Nature IF: 42.778）

Seki Takahiro,Yang Yunlong,Sun Xiaoting et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism.[J] .Nature, 2022, 608: 421-428.

Abstract 摘要

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes. 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.

葡萄糖的摄取对癌症的糖酵解至关重要，并参与脂肪组织的非颤抖性生热1-6。大多数癌症利用糖酵解来为其无限的生长、入侵和转移提供能量2,7,8。寒冷和药物激活棕色脂肪组织（BAT）的生热代谢，促进脂肪细胞的血糖摄取4,5,9。然而，与BAT激活相关的全球代谢变化对肿瘤生长的功能影响尚不清楚。在这里，我们表明，将肿瘤小鼠暴露在寒冷条件下，可明显抑制各种类型的实体瘤的生长，包括临床上无法治疗的癌症，如胰腺癌。从机制上讲，寒冷诱导的BAT激活大大降低了血糖，阻碍了癌细胞中基于糖酵解的代谢。移除BAT并在寒冷环境下喂食高糖饮食可恢复肿瘤生长，而BAT生热的关键转录中介体Ucp1在基因上的删除使寒冷触发的抗癌作用失效。在一项试验性的人体研究中，温和的冷暴露激活了健康人和一名癌症患者的大量BAT，并减轻了肿瘤组织中的葡萄糖摄取量。这些发现为癌症治疗提供了一个以前未曾描述过的概念和范式，采用了一种简单而有效的方法。我们预计，通过任何其他方法，如单独或与其他抗癌疗法相结合的药物和设备，冷暴露和激活BAT，将为有效治疗各种癌症提供一种通用方法。