Endocrine Abstracts

Cushing’s syndrome (CS) is a hormonal disorder characterized by chronic high levels of circulating cortisol. Patients treated for CS develop chronic adrenal insufficiency (AI) and hypothalamus-pituitary-adrenal (HPA) axis dysfunction. Long-term treatment with glucocorticoids (GC) is mandatory to overcome AI. Fibroblast growth factor (FGF) -21, 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 adrenal gland in a mouse model with AI post chronic hypercortisolism. Male mice received corticosterone (CORT) or vehicle (VEH) in the drinking water for 5wks, followed by a 3d tapering period. After this period, the animals developed AI post-CS and were injected daily with recombinant FGF21 for 7d. Plasma circadian and stimulated CORT and ACTH levels were assessed by immunoassay. Adrenal proliferation was determined by Ki67 staining. Genes from the liver and adrenal gland were determined by qPCR. During active Cushing, CORT-treated mice displayed a decreased fasting plasma glucose compared to VEH due to basal hyperinsulinemia that maintains even during the glucose tolerance test. After treatment, AI-FGF21group were challenged with FGF21, and at 3h they presented a lower ACTH/CORT ratio than the AI-VEH group meaning that their adrenals are more responsive to ACTH. As expected, during the nocturnal circadian cycle and hypoglycemia, AI-groups had decreased plasma CORT levels than CTL groups. Interestingly, AI-FGF21 mice display higher CORT plasma levels with higher Fgf21 liver expression during the circadian cycle than AI-VEH mice. Moreover, the number of proliferating cortical adrenal cells, identified by Ki67 staining, was higher in the AI groups than in CTL groups, although there was no difference between the AI groups. In line with this result, AI groups maintained upregulated stem/progenitor markers compared with their respective treatment CTL groups. Interestingly, in hypoglycemic conditions, AI-FGF21 mice presented higher adrenal Sonic hedgehog (Shh) expression levels than CTL-FGF21 and AI-VEH mice. 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.