Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop

Mol Endocrinol. 2015 Feb;29(2):213-23. doi: 10.1210/me.2014-1259. Epub 2014 Dec 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex / cytology
  • Adrenal Cortex / metabolism
  • Adrenocorticotropic Hormone / pharmacology
  • Animals
  • Base Pairing
  • Binding Sites
  • Chromatin / metabolism
  • Corticosterone / biosynthesis
  • Dexamethasone / pharmacology
  • Fibroblast Growth Factors / metabolism*
  • Genetic Loci
  • Glucocorticoids / pharmacology*
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • PPAR alpha / metabolism
  • Protein Binding / drug effects
  • Receptors, Glucocorticoid / metabolism
  • Transcription Initiation Site
  • Transcriptional Activation / drug effects


  • Chromatin
  • Glucocorticoids
  • PPAR alpha
  • Receptors, Glucocorticoid
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Corticosterone