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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.
Afiliação
  • Cimino I; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Kim H; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA 02139.
  • Tung YCL; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Pedersen K; Global Obesity and Liver Disease Research, Novo Nordisk A/S, DK-2760 Maaloev, Denmark.
  • Rimmington D; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Tadross JA; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Kohnke SN; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
  • Neves-Costa A; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Barros A; Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
  • Joaquim S; Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
  • Bennett D; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA 02139.
  • Melvin A; Biostatistics, Early Clinical Development, Pfizer Inc., Cambridge, MA 02139.
  • Lockhart SM; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Rostron AJ; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Scott J; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
  • Liu H; Integrated Critical Care Unit, Sunderland Royal Hospital, South Tyneside and Sunderland NHS Foundation Trust, Sunderland SR4 7TP, United Kingdom.
  • Burling K; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
  • Barker P; Kymab Ltd., Cambridge CB22 3AT, United Kingdom.
  • Clatworthy MR; Core Biochemical Assay Laboratories, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom.
  • Lee EC; Core Biochemical Assay Laboratories, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom.
  • Simpson AJ; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.
  • Yeo GSH; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
  • Moita LF; Cellular Genetics, Wellcome Sanger Institute, Hinxton CB10 1RQ, United Kingdom.
  • Bence KK; Kymab Ltd., Cambridge CB22 3AT, United Kingdom.
  • Jørgensen SB; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
  • Coll AP; Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, United Kingdom.
  • Breen DM; Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
  • O'Rahilly S; Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Article em En | MEDLINE | ID: mdl-34187898
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sistema Hipófise-Suprarrenal / Fator 15 de Diferenciação de Crescimento / Sistema Hipotálamo-Hipofisário Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sistema Hipófise-Suprarrenal / Fator 15 de Diferenciação de Crescimento / Sistema Hipotálamo-Hipofisário Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido