GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

恶病质 脂肪组织 白色脂肪组织 浪费的 脂肪细胞 内分泌学 癌症 内科学 癌症研究 生物 医学
作者
Xu Chen,Qingnan Wu,Wei Gong,Shaolong Ju,Jiawen Fan,Xiaohan Gao,Xingyang Liu,Lei Xiao,Бо Лю,Xiangdong Ming,Qianyu Wang,Ming Fu,Yongmei Song,Yan Wang,Qimin Zhan
出处
期刊:Signal Transduction and Targeted Therapy [Springer Nature]
卷期号:9 (1)
标识
DOI:10.1038/s41392-024-01950-w
摘要

Abstract Cachexia, which affects 50–80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75–ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone , a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.
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