Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2021-07, Vol.118 (27), p.1

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 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 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.