Glucocorticoids Regulate the Metabolic Hormone FGF21 in a Feed-Forward Loop

Abstract

Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-α, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-α ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.

FGF21 and the late adaptive response to starvation in humans

“…The analysis suggesting an association between AST and FGF21 during fasting is thus consistent with the concept that FGF21 has a role in the latter stages of the human adaptive starvation response, when tissue stress becomes evident by transaminase release and when glucose homeostasis is increasingly reliant on the shunting of liberated amino acids to gluconeogenesis in the liver. The role of FGF21 and peripheral tissue fuel shifting in the late starvation response is also strongly supported by investigations in mice (3,5,34). Therefore, unlike ketogenesis, this link between FGF21 and the late starvation response in humans suggests this as a conserved physiological role for fasting-induced FGF21.…”

Curcumin and dietary polyphenol research: beyond drug discovery

“…For this purpose, we have adopted a dexamethasone-induced insulin resistance mouse model [37] . Briefly, C57BL/6J mice fed a regular diet were administered daily intraperitoneal dexamethasone injections with or without daily curcumin gavage for 5 days.…”

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

“…Conversely, GR␣ overexpression caused a significant (p Ͻ 0.01) increase in PPAR␣ transcriptional activity. Glucocorticoids have been shown to regulate FGF21 expression in a feed-forward loop (41). To determine whether GR␤ or GR␣ can regulate FGF21 expression, we measured luciferase activity of the FGF21 promoter construct (FGF21-Luc) with GR␤ or GR␣ overexpressed.…”