{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:03:34Z","timestamp":1790352214008,"version":"4.1.0"},"reference-count":310,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["314061271-TRR 205"],"award-info":[{"award-number":["314061271-TRR 205"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["Re 752\/30-1"],"award-info":[{"award-number":["Re 752\/30-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 behavior, suppress food intake, and induce nausea and vomiting during cellular stress, GDF-15 signals via a brainstem-restricted receptor, glial cell line-derived neurotrophic factor family receptor alpha like (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\u2013GFRAL antagonism is being pursued as a therapeutic strategy. Recent studies have highlighted a dynamic interplay between GDF-15 and the hypothalamus\u2013pituitary\u2013adrenal (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 discusses the hypothesis that downstream glucocorticoid signaling that 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 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.<\/jats:p>","DOI":"10.1210\/endrev\/bnag035","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:03:44Z","timestamp":1789473824000},"source":"Crossref","is-referenced-by-count":0,"title":["The sentinel hormone growth and differentiation factor-15, glucocorticoid homeostasis, and adrenal disorders"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9333-5189","authenticated-orcid":false,"given":"Ilaria","family":"Bonaventura","sequence":"first","affiliation":[{"name":"Department of Internal Medicine IV, LMU Hospital, LMU Munich , Munich 80336 ,","place":["Germany"]},{"name":"Department of Experimental Medicine, Sapienza University of Rome , Rome 00161 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5873-8567","authenticated-orcid":false,"given":"Isabel","family":"Weigand","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, LMU Hospital, LMU Munich , Munich 80336 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M","family":"Isidori","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome , Rome 00161 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kroiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, LMU Hospital, LMU Munich , Munich 80336 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9817-9875","authenticated-orcid":false,"given":"Martin","family":"Reincke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, LMU Hospital, LMU Munich , Munich 80336 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"issue":"21","key":"2026092511111632800_bnag035-B1","doi-asserted-by":"crossref","first-page":"11514","DOI":"10.1073\/pnas.94.21.11514","article-title":"MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily","volume":"94","author":"Bootcov","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7675","key":"2026092511111632800_bnag035-B2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nature24042","article-title":"Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15","volume":"550","author":"Hsu","year":"2017","journal-title":"Nature"},{"issue":"10","key":"2026092511111632800_bnag035-B3","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1093\/emboj\/19.10.2212","article-title":"The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1","volume":"19","author":"Bauskin","year":"2000","journal-title":"EMBO J"},{"issue":"4948","key":"2026092511111632800_bnag035-B4","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1126\/science.2315700","article-title":"Requirement for activin A and transforming growth factor-beta 1 pro-regions in homodimer assembly","volume":"247","author":"Gray","year":"1990","journal-title":"Science"},{"key":"2026092511111632800_bnag035-B5","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3389\/fimmu.2020.00951","article-title":"Growth\/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint","volume":"11","author":"Wischhusen","year":"2020","journal-title":"Front Immunol"},{"issue":"1","key":"2026092511111632800_bnag035-B6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev-physiol-022020-045449","article-title":"The GDF15-GFRAL pathway in health and metabolic disease: friend or foe?","volume":"83","author":"Breit","year":"2021","journal-title":"Annu Rev Physiol"},{"issue":"4","key":"2026092511111632800_bnag035-B7","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1210\/endrev\/bnad004","article-title":"Intracellular to interorgan mitochondrial communication in striated muscle in health and disease","volume":"44","author":"Boardman","year":"2023","journal-title":"Endocr Rev"},{"issue":"4","key":"2026092511111632800_bnag035-B8","doi-asserted-by":"crossref","first-page":"bnaa007","DOI":"10.1210\/endrev\/bnaa007","article-title":"GDF15: a hormone conveying somatic distress to the brain","volume":"41","author":"Lockhart","year":"2020","journal-title":"Endocr Rev"},{"issue":"6220","key":"2026092511111632800_bnag035-B9","doi-asserted-by":"crossref","DOI":"10.1126\/science.1260419","article-title":"Proteomics. 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