Cold exerts anti-tumor effects by activating brown adipose tissue

In order to adapt to their energy needs, tumors exhibit unique metabolic characteristics that allow for the production of ATP in the form of aerobic glycolysis to supply energy for cellular activities. Compared to mitochondrial respiration, aerobic glycolysis is much less efficient. As a result, tumor cells take up large amounts of glucose from the body to provide energy for their growth, invasion, and metastasis.

Brown adipose tissue is a specific thermogenic tissue that plays an important role in maintaining body temperature in mammals with its high expression of uncoupling protein 1 (UCP1). Brown adipose tissue can be activated in adults when exposed to cold stimuli or pharmacological interventions. Under the control of sympathetic signaling, brown adipocytes can uncouple the electron transfer process in the oxidative transfer respiratory chain from ATP production via UCP1, thereby converting the mitochondrial transmembrane proton gradient into heat release, a process known as non-shivering thermogenesis (NST).

Similar to tumor cells, brown adipocytes rapidly and efficiently utilize nutrients such as glucose as a key metabolic substrate for thermogenesis. Based on this mechanism, brown adipose activation and thermogenesis have emerged as potential therapies for regulating blood glucose and treating metabolic diseases such as obesity and type 2 diabetes, and some progress has been made in clinical studies. However, the therapeutic potential of brown fat in other major disease areas remains to be explored. It is worth mentioning that both brown fat and tumors share the commonality of high glucose uptake, but the academic community still knows little about brown adipose tissue and its relationship with tumors.

In August 2022, researchers from Karolinska Institutet in Sweden, in collaboration with researchers from Fudan University, Shandong University, and Wenzhou Medical University, published a research paper in Nature entitled "Brown-fat-mediated tumor suppression by cold-altered global metabolism".

The study puts forward a new concept that cold activates brown fat to inhibit tumor growth and gives a corresponding treatment idea.

In order to explore the effect of cold on tumor development, the research team first constructed various transplantation tumor models such as colorectal cancer, pancreatic cancer, melanoma, and other solid tumor models such as the colorectal cancer spontaneous tumor model and the breast cancer spontaneous tumor model in mice, applied different temperatures to intervene, and found that, compared with the thermo-neutral 30 °C treatment group, exposure to cold at 4 °C significantly inhibited the growth of tumors and prolonged the survival period of the tumor-bearing mice. Using a non-solid tumor model in which the core body temperature remained at 37°C, the team ruled out a direct effect of cold on solid tumors and found a decrease in microvessel density and an increase in apoptosis within the tumors.

The team further observed that brown fat was significantly activated in mice exposed to cold, and PET-CT results showed that cold exposure significantly promoted glucose uptake from brown fat in hormonal mice and, conversely, significantly inhibited glucose uptake in tumors. Further, brown fat removal effectively reversed the cold inhibition of tumor growth. Gene enrichment and metabolomic analyses showed that cold exposure resulted in a significant upregulation of glucose metabolism in brown adipose tissue. In contrast, glucose metabolism was significantly inhibited in tumor tissues, and both PI3K and mTOR signals were downregulated.

The results suggest that cold activation of brown adipose tissue effectively inhibits tumor growth by reducing the source of glucose and impairing the tumor's ability to take up glucose through glucose competition. The team then validated this mechanism using a high-glucose-fed hormonal mouse model and a Ucp1 knockout hormonal mouse model.

Finally, the team recruited healthy volunteers and tumor patients on a small scale for prospective clinical observation. The results demonstrated that healthy volunteers and tumor patients had sufficient amounts of brown fat and could be activated by cold. Meanwhile, after one week of mild cold exposure, the tumor patients showed significant activation of brown adipose tissue and increased glucose uptake, while on the contrary, glucose uptake was decreased in the tumor tissue of the patients, suggesting the clinical feasibility of applying cold interventions to treat tumors.Ucp1

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