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

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ID: 328848
2026
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Abstract
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.
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openalex_W7213411045 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ilaria Bonaventura, Isabel Weigand, Andrea M. Isidori, Matthias Kroiß, Martín Reincke
Journal endocrine reviews
Year 2026
DOI
10.1210/endrev/bnag035
URL
https://doi.org/10.1210/endrev/bnag035
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