Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15
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 p...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271778/ https://www.ncbi.nlm.nih.gov/pubmed/34187898 http://dx.doi.org/10.1073/pnas.2106868118 |
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author | Cimino, Irene Kim, Hanna Tung, Y. C. Loraine Pedersen, Kent Rimmington, Debra Tadross, John A. Kohnke, Sara N. Neves-Costa, Ana Barros, André Joaquim, Stephanie Bennett, Don Melvin, Audrey Lockhart, Samuel M. Rostron, Anthony J. Scott, Jonathan Liu, Hui Burling, Keith Barker, Peter Clatworthy, Menna R. Lee, E-Chiang Simpson, A. John Yeo, Giles S. H. Moita, Luís F. Bence, Kendra K. Jørgensen, Sebastian Beck Coll, Anthony P. Breen, Danna M. O’Rahilly, Stephen |
author_facet | Cimino, Irene Kim, Hanna Tung, Y. C. Loraine Pedersen, Kent Rimmington, Debra Tadross, John A. Kohnke, Sara N. Neves-Costa, Ana Barros, André Joaquim, Stephanie Bennett, Don Melvin, Audrey Lockhart, Samuel M. Rostron, Anthony J. Scott, Jonathan Liu, Hui Burling, Keith Barker, Peter Clatworthy, Menna R. Lee, E-Chiang Simpson, A. John Yeo, Giles S. H. Moita, Luís F. Bence, Kendra K. Jørgensen, Sebastian Beck Coll, Anthony P. Breen, Danna M. O’Rahilly, Stephen |
author_sort | Cimino, Irene |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8271778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-82717782021-07-16 Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 Cimino, Irene Kim, Hanna Tung, Y. C. Loraine Pedersen, Kent Rimmington, Debra Tadross, John A. Kohnke, Sara N. Neves-Costa, Ana Barros, André Joaquim, Stephanie Bennett, Don Melvin, Audrey Lockhart, Samuel M. Rostron, Anthony J. Scott, Jonathan Liu, Hui Burling, Keith Barker, Peter Clatworthy, Menna R. Lee, E-Chiang Simpson, A. John Yeo, Giles S. H. Moita, Luís F. Bence, Kendra K. Jørgensen, Sebastian Beck Coll, Anthony P. Breen, Danna M. O’Rahilly, Stephen Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2021-07-06 2021-06-29 /pmc/articles/PMC8271778/ /pubmed/34187898 http://dx.doi.org/10.1073/pnas.2106868118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Cimino, Irene Kim, Hanna Tung, Y. C. Loraine Pedersen, Kent Rimmington, Debra Tadross, John A. Kohnke, Sara N. Neves-Costa, Ana Barros, André Joaquim, Stephanie Bennett, Don Melvin, Audrey Lockhart, Samuel M. Rostron, Anthony J. Scott, Jonathan Liu, Hui Burling, Keith Barker, Peter Clatworthy, Menna R. Lee, E-Chiang Simpson, A. John Yeo, Giles S. H. Moita, Luís F. Bence, Kendra K. Jørgensen, Sebastian Beck Coll, Anthony P. Breen, Danna M. O’Rahilly, Stephen Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title | Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title_full | Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title_fullStr | Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title_full_unstemmed | Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title_short | Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15 |
title_sort | activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous gdf15 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271778/ https://www.ncbi.nlm.nih.gov/pubmed/34187898 http://dx.doi.org/10.1073/pnas.2106868118 |
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