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

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.

The Role of GDF15 as a Myomitokine

“…This suggests that GDF15 might be effective to induce stress and anxiety. This fits with recent observations in rodent models that exogenous GDF15 application as well as activation of endogenous GDF15 by genotoxic or endoplasmic reticulum toxins led to an activation of the hypothalamic–pituitary–adrenal (HPA) stress axis, which was absent in GDF15 −/− [ 50 ]. In a mouse model of GDF15 induction as a myomitokine, we could show that endogenous activation of the GDF15–GFRAL pathway leads to increased anxiety related behavior and induces a day-time restricted anorexia by increased hypothalamic corticotropin releasing hormone (CRH) acting via CRH receptor 1 [ 51 ].…”

“…A recent publication reported that GDF15 activates the HPA axis, resulting in increased circulating glucocorticoids (corticosterone in rodents, cortisol in humans) [ 50 ]. One of the key functions of corticosterone/cortisol is to increase blood glucose levels by increasing hepatic glucose output.…”

Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

“…While our data clearly support the notion of an induction of hypothalamic CRH by GDF15-GFRAL signaling, our mouse model of chronic elevated GDF15 shows that chronic activation of the GDF15-GFRAL pathway might increase stress susceptibility but does not induce a sustained increase of corticosterone levels. Importantly, while acute administration of recombinant GDF15 promotes supraphysiological plasma GDF15 levels of >30ng/ml after 1-hr and >10ng/ml 4-hrs post -treatment in mice 38 , circulating GDF15 levels in TG mice oscillate in a range of 0.35 -1.4ng/ml (Fig. 1b,d) in a circadian manner.…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 24, 2021. ; https://doi.org/10.1101/2021.09.22.461199 doi: bioRxiv preprint 8 chronic elevated GDF15 shows that chronic activation of the GDF15-GFRAL pathway might increase stress susceptibility but does not induce a sustained increase of corticosterone levels. Importantly, while acute administration of recombinant GDF15 promotes supraphysiological plasma GDF15 levels of >30ng/ml after 1-hr and >10ng/ml 4-hrs post -treatment in mice 38 , circulating GDF15 levels in TG mice oscillate in a range of 0.35 -1.4ng/ml (Fig. 1b,d) in a circadian manner.…”

“…Only in male TG mice the stress induced increase in corticosterone was augmented. It was recently shown that an acute elevation of endogenous or recombinant GDF15 in mice and rats leads to an activation of the HPA axis evidenced by highly increased corticosterone levels 4 to 6 hours after treatment 38 . While our data clearly support the notion of an induction of hypothalamic CRH by GDF15-GFRAL signaling, our mouse model of chronic elevated GDF15 shows that chronic activation of the GDF15-GFRAL pathway might increase stress susceptibility but does not induce a sustained increase of corticosterone levels.…”