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

Rucha Patel, Angie L. Bookout, Lilia Magomedova, Bryn M. Owen, Giulia P. Consiglio, Makoto Shimizu, Yuan Zhang, David J. Mangelsdorf, Steven A. Kliewer, Carolyn L. Cummins

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)213-223
Number of pages11
JournalMolecular Endocrinology
Issue number2
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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