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Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15

Lookup NU author(s): Dr Anthony RostronORCiD, Jonathan Scott, Professor John SimpsonORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 National Academy of Sciences. All rights reserved.An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

Publication metadata

Author(s): Cimino I, Kim H, Tung YCL, Pedersen K, Rimmington D, Tadross JA, Kohnke SN, Neves-Costa A, Barros A, Joaquim S, Bennett D, Melvin A, Lockhart SM, Rostron AJ, Scott J, Liu H, Burling K, Barker P, Clatworthy MR, Lee E-C, Simpson AJ, Yeo GSH, Moita LF, Bence KK, Jorgensen SB, Coll AP, Breen DM, O'Rahilly S

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2021

Volume: 118

Issue: 27

Print publication date: 06/07/2021

Online publication date: 29/06/2021

Acceptance date: 02/04/2018

Date deposited: 19/07/2021

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences


DOI: 10.1073/pnas.2106868118


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