Abstract
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.
Highlights
The activation of the hypothalamic–pituitary–adrenal (HPA) axis, which results in an increase in circulating glucocorticoids, is a stereotypical response to a wide range of stressful stimuli
Since its identification in 1997 as a novel endocrine member of the TGF-β superfamily expressed in activated macrophages [40], circulating levels of GDF15 have been reported to be elevated in a broad spectrum of conditions, including many disease states
We describe another important action of GDF15, namely the activation of the hypothalamic– pituitary–adrenal (HPA) axis
Summary
The activation of the hypothalamic–pituitary–adrenal (HPA) axis, which results in an increase in circulating glucocorticoids, is a stereotypical response to a wide range of stressful stimuli. Earlier literature contains several reports of increases in circulating glucocorticoid levels in rodents occurring in response to a range of toxins, including honey bee and snake venom [6, 7], cyanide [8], and purified diphtheria toxin [8]. Genotoxins such as cisplatin have been shown to activate the HPA axis in dogs and rats [9, 10]. GDF15 is currently being explored as an antiobesity drug and examination of the degree and duration of the steroid effect will need to be incorporated into any human trials
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