期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2106868118
关键词
gdf15; corticosteroids; stress; toxins; adrenal
资金
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Pfizer Worldwide Research, Development, and Medical Postdoctoral training program
- Medical Research Council (MRC Metabolic Diseases Unit) [MC_UU_00014/1]
- NIHR Clinical Lectureship [CL-2019-14-504]
- European Commission Horizon 2020 [ERC-2014-CoG 647888-iPROTECTION]
- Wellcome Trust Investigator Award [220268/Z/20/Z]
- Histopathology Core (MRC Metabolic Diseases Unit) [MC_UU_00014/5]
- Histopathology Core (Wellcome Trust Strategic Award) [100574/Z/12/Z]
- Wellcome Trust [WT 107064, WT 095515/Z/11/Z]
- MRC Metabolic Disease Unit [MC_UU_00014/1]
- NIHR Rare Disease Translational Research Collaboration
- MRC SHIELD Antimicrobial Resistance Consortium
- NIHR Cambridge Biomedical Research Centre
- MRC [MC_UU_00014/1] Funding Source: UKRI
- Wellcome Trust [220268/Z/20/Z, 095515/Z/11/Z] Funding Source: Wellcome Trust
GDF15 plays a crucial role in activating the hypothalamic-pituitary-adrenal (HPA) axis; It is essential for the protective HPA response to toxins that do not induce a substantial cytokine response.
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 alpha-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据