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 ca...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.展开更多
基金National Key Research and Development Program of China#1 under Y.W.[number 2022YFC3400904]National Natural Science Foundation of China#2 under Q.Z.[number 81988101 and 81830086]+2 种基金National Natural Science Foundation of China#3 under Y.W.[number 82173152]Research Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,CAMS Innovation Fund for Medical Sciences#4 under Q.Z.[number 2019-I2M-5-081]Science Foundation of Peking University Cancer Hospital#5 under Q.Z.[number 17-01].
文摘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.
