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

Cimino, Irene ; Kim, Hanna ; Tung, YC 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 SH ; Moita, Luís F ; Bence, Kendra K ; Jørgensen, Sebastian Beck ; Coll, Anthony P ; Breen, Danna M ; O'Rahilly, Stephen

http://dx.doi.org/10.1073/pnas.2106868118 2021-07

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  • Título:
    Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15
  • Autor: Cimino, Irene ; Kim, Hanna ; Tung, YC 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 SH ; Moita, Luís F ; Bence, Kendra K ; Jørgensen, Sebastian Beck ; Coll, Anthony P ; Breen, Danna M ; O'Rahilly, Stephen
  • Assuntos: adrenal ; Animals ; Cisplatin ; corticosteroids ; Endoplasmic Reticulum Stress ; gdf15 ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; Glucocorticoids ; Growth Differentiation Factor 15 ; Humans ; Hypothalamo-Hypophyseal System ; Lipopolysaccharides ; Mice ; Pituitary-Adrenal System ; Rats ; stress ; toxins ; Tunicamycin
  • Descrição: 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. This project is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and by the Pfizer Worldwide Research, Development and Medical Postdoctoral training program.The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. A.P.C., D. R., J.A.T., I.C., Y.C.L.T. and G.S.H.Y. are supported by the Medical Research Council (MRC Metabolic Diseases Unit (MC_UU_00014/1). J.A.T. is supported by the NIHR Clinical Lectureship (CL-2019-14-504). L.F.M. was supported by the European Commission Horizon 2020 (ERC-2014-CoG 647888- iPROTECTION). M.R.C. is supported by a Wellcome Trust Investigator Award (220268/Z/20/Z). Mouse mantainence in Cambridge are supported by Gemini Chu and Hayley Forest, with pathology support from J. Warner and the Histopathology Core (MRC Metabolic Diseases Unit (MC_UU_00014/5) and Wellcome Trust Strategic Award (100574/Z/12/Z). S.O.R. is supported by the Wellcome Trust (WT 107064 and WT 095515/Z/11/Z), the MRC Metabolic Disease Unit (MC_UU_00014/1) and The National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and NIHR Rare Disease Translational Research Collaboration.Professor Simpson is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care. AJR and AJS are supported by the MRC SHIELD Antimicrobial Resistance Consortium.
  • Editor: http://dx.doi.org/10.1073/pnas.2106868118
  • Data de criação/publicação: 2021-07
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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