Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.
Yuexiao TangTao YaoXin TianXintong XiaXingxiao HuangZhewen QinZhong ShenLin ZhaoYaping ZhaoBowen DiaoYan PingXiaoxiao ZhengYonghao XuHui ChenTao QianTao MaBen ZhouJianping WengQimin ZhouYong LiuMengle ShaoWei ChenBo ShanYing WuPublished in: The Journal of experimental medicine (2024)
Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.
Keyphrases
- chemotherapy induced
- weight loss
- endoplasmic reticulum stress
- bariatric surgery
- roux en y gastric bypass
- body weight
- gastric bypass
- poor prognosis
- locally advanced
- drug delivery
- mental health
- public health
- cancer therapy
- type diabetes
- binding protein
- emergency department
- obese patients
- glycemic control
- gene expression
- photodynamic therapy
- social media
- long non coding rna
- weight gain
- dna methylation
- adipose tissue
- climate change
- drug induced
- protein protein
- small molecule