Endocrine Abstracts

Objective: After Cushing Syndrome (CS) is cured, up to 70% of patients develop chronic adrenal insufficiency (AI) and hypothalamus-pituitary-adrenal (HPA) axis dysfunction. A long-term treatment with glucocorticoids (GC) is mandatory to overcome AI. However, this treatment implies non-desired complications. Fibroblast growth factor (FGF21), a key regulator of metabolism, has a bidirectional relationship with GC that bypasses the negative feedback of the HPA axis. In this study, we aimed to investigate the potential effects of FGF21 treatment in the HPA axis in a mouse model with AI post-CS.

Methods: Male C57B6/J mice (n=10/group) received corticosterone (CORT) (500μg/mL) or vehicle (VEH) in the drinking water for 5 weeks, followed by 3 days tapering period. After this period, the animals developed AI post-CS, and then they were injected daily intraperitoneally with recombinant FGF21 or VEH for 7 days. Plasma circadian and stimulated CORT and ACTH levels were assessed by immunoassay. Steroidogenic and stem/progenitor genes in the adrenal gland were determined by qPCR.

Results: AI mice during the nocturnal circadian cycle had decreased plasma CORT levels and down-regulated adrenal steroidogenic genes, whereas plasma ACTH levels remained similar to non-treated (CTL) mice. Three hours after FGF21 administration, CTL-FGF21 and CTL-VEH had similar plasma ACTH levels. However, plasma CORT levels in the CTL-FGF21 mice were significantly increased compared with CTL-VEH mice. As expected, AI groups showed lower plasma CORT levels than CTL mice. Remarkably, between the AI groups, at 1 h the FGF21 treated mice exhibited higher plasma CORT levels and maintained significantly higher ACTH levels during the 3 h after FGF21 administration compared with the VEH group. CTL mice treated with FGF21 for 7 days, increased their circadian and hypoglycemic stimulated plasma CORT levels compared to the CTL-VEH group. In line with this result, the expression of adrenal steroidogenic genes (StAR, Cyp11a1, and Cyp11b1) and stem/progenitor markers (Gli, Wt1, Wnt4, and Dlk) were upregulated in the CTL-FGF21 group. In agreement with CORT withdraw, AI groups maintained lower plasma CORT levels in circadian and hypoglycemic conditions, together with upregulated stem/progenitor markers compared with their respective treatment CTL groups. Interestingly, under hypoglycemic conditions, AI-FGF21 mice presented higher expression levels of adrenal Sonic hedgehog (Shh) than CTL-FGF21 and AI-VEH mice.

Conclusion: Our data describe that FGF21 contributes to maintaining a sustained CORT secretion and suggests that FGF21 accelerates and supports the adrenocortical cell renewal during AI.