ABSTRACT
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.
Subject(s)
Anorexia , Doxorubicin , Endoribonucleases , Growth Differentiation Factor 15 , Liver , Protein Serine-Threonine Kinases , Weight Loss , X-Box Binding Protein 1 , Animals , Humans , Mice , Anorexia/chemically induced , Anorexia/metabolism , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Doxorubicin/adverse effects , Endoribonucleases/metabolism , Endoribonucleases/genetics , Growth Differentiation Factor 15/adverse effects , Growth Differentiation Factor 15/genetics , Growth Differentiation Factor 15/metabolism , Liver/metabolism , Liver/drug effects , Liver/pathology , Mice, Inbred C57BL , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Signal Transduction/drug effects , Unfolded Protein Response/drug effects , Weight Loss/drug effects , X-Box Binding Protein 1/metabolism , X-Box Binding Protein 1/geneticsABSTRACT
BACKGROUND: With the exploding prevalence of obesity, many children are at risk of developing nonalcoholic fatty liver disease. Using anthropometric and laboratory parameters, our study aimed to develop a model to quantitatively evaluate liver fat content (LFC) in children with obesity. METHODS: A well-characterized cohort of 181 children between 5 and 16 years of age were recruited to the study in the Endocrinology Department as the derivation cohort. The external validation cohort comprised 77 children. The assessment of liver fat content was performed using proton magnetic resonance spectroscopy. Anthropometry and laboratory metrics were measured in all subjects. B-ultrasound examination was carried out in the external validation cohort. The Kruskal-Wallis test, Spearman bivariate correlation analyses, univariable linear regressions and multivariable linear regression were used to build the optimal predictive model. RESULTS: The model was based on indicators including alanine aminotransferase, homeostasis model assessment of insulin resistance, triglycerides, waist circumference and Tanner stage. The adjusted R2 of the model was 0.589, which presented high sensitivity and specificity both in internal [sensitivity of 0.824, specificity of 0.900, area under curve (AUC) of 0.900 with a 95% confidence interval: 0.783-1.000] and external validation (sensitivity of 0.918 and specificity of 0.821, AUC of 0.901 with a 95% confidence interval: 0.818-0.984). CONCLUSIONS: Our model based on five clinical indicators was simple, non-invasive, and inexpensive; it had high sensitivity and specificity in predicting LFC in children. Thus, it may be useful for identifying children with obesity who are at risk for developing nonalcoholic fatty liver disease.
