Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

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.

Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control.

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

Growth Differentiation Factor-15 Based ABC (Age, Biomarkers, Clinical History)-AF (Atrial Fibrillation)-Bleeding Risk Score for Elderly Patients with Nonvalvular Atrial Fibrillation.

Background: Growth differentiation factor-15 (GDF-15) is a strong predictor of bleeding in atrial fibrillation (AF) patients. The novel ABC (age, biomarkers, and clinical history), AF, and bleeding risk score outperforms HAS-BLED bleeding risk score for major bleeding (MB) in patients with AF receiving oral anti-coagulation in the clinical trial cohort. However, it has not been entirely externally validated. We aimed to refine and understand the application of the ABC-AF bleeding risk score in elderly (aged ≥65 years old) patients with nonvalvular atrial fibrillation (NVAF) for predicting the different types of bleeding events and anti-thrombotic treatments. Methods: We identified elderly patients with NVAF between March 2018 and December 2019 who were hospitalized for the first time after a diagnosis of NVAF. We measured the plasma concentration of the ABC biomarkers (growth differentiation factor 15 (GDF-15) and cardiac troponin-T (cTnT)) from enrolled patients. We collected their general information and follow up for one year until December 2020. During the follow-up period, information on the occurrence of bleeding events (major bleeding, clinically relevant nonmajor gastrointestinal bleeding (CRNM GIB), and minor bleeding events) was collected. Results: We enrolled 342 elderly NAVF patients; the ABC-AF bleeding and HAS-BLED scores were quantified. With an average of 1.5 years of follow-up, 6 patients had an intracranial hemorrhage; 57 patients had CRNM GIB; and 68 patients had minor bleeding events (36 fecal occult blood positive and 32 other minor bleeding events). The ABC-AF bleeding score yielded a C-index of 0.72 (95% CI 0.60-0.84) for predicting MB in elderly patients with NAVF, C-index of 0.69 (95% CI 0.57-0.82) by HAS-BLED score. Comparison of the incidence of bleeding events during follow-up and the predicted 1-year incidence of bleeding events by each bleeding risk score, ABC-AF bleeding, and HAS-BLED scores have similar value in predicting the risk for elderly patients with NAVF in different types of bleeding events, whether on oral anti-coagulation treatment (OAC) or non-OAC (P > 0.05). Conclusion: In elderly patients with NVAF, the biomarker-based ABC-AF bleeding score showed similar performance compared with the HAS-BLED bleeding risk score.

GDF15 Induces Anorexia through Nausea and Emesis.

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry.

Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15.

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.