title: 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.
authors.affiliation: Department of Pharmaceutical Sciences (R.P., L.M., G.P.C., C.L.C.), University of Toronto, Toronto, Ontario, Canada M5S 3M2; Department of Pharmacology and Howard Hughes Medical Institute (A.L.B., B.M.O., M.S., Y.Z., D.J.M.), and Department of Molecular Biology (S.A.K.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Banting and Best Diabetes Centre (C.L.C.), Toronto, Ontario, Canada M5G 2C4.
authors.forename: Rucha
authors.initials: R
authors.lastname: Patel
authors.forename: Angie L
authors.initials: AL
authors.lastname: Bookout
authors.forename: Lilia
authors.initials: L
authors.lastname: Magomedova
authors.forename: Bryn M
authors.initials: BM
authors.lastname: Owen
authors.forename: Giulia P
authors.initials: GP
authors.lastname: Consiglio
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D020029:Base Pairing; D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism; D003345:Corticosterone / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D056426:Genetic Loci; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D047493:PPAR alpha / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D024363:Transcription Initiation Site; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002843:Chromatin; D005938:Glucocorticoids; D047493:PPAR alpha; D011965:Receptors, Glucocorticoid; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone