The Sentinel Hormone GDF-15, Glucocorticoid Homeostasis and Adrenal Disorders

Growth and differentiation factor 15 (GDF-15) is a stress-responsive hormone secreted by various cell types in response to cellular stress. To regulate ingestive behaviour, suppress food intake, and induce nausea and vomiting during cellular stress, GDF-15 signals via a brainstem-restricted receptor, GFRAL. Elevated circulating GDF-15 levels serve as a biomarker of cellular stress and are increased in a wide range of diseases. GDF-15 has recently been established as a causal factor in cancer cachexia and GDF15-GFRAL antagonism is being pursued as a therapeutic strategy. Recent studies have highlighted a dynamic interplay between GDF-15 and the hypothalamus-pituitary-adrenal (HPA) axis, suggesting that GDF-15 acts as a sentinel hormone in stress responses. Here, we review the canonical role of GDF-15 in stress-related conditions and its potential impact on circadian regulation and HPA axis dysregulation. The review explores the potential activation of the HPA axis by GDF-15 and discuss the hypothesis that downstream glucocorticoid signalling may contribute to some of the cardiovascular, metabolic, immune, and musculoskeletal changes reported for GDF-15. Additionally, the review discusses the potential role of GDF-15 in adrenal insufficiency and its treatment and in adrenocortical carcinoma. In summary, this review aims to elucidate the role of GDF-15 in glucocorticoid homeostasis and adrenal disease in the context of the stress response.