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 +9 more
TLDR
FGF21 and GCs regulate each other's production in a feed-forward loop and it is suggested that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.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.read more
Citations
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Journal ArticleDOI
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
TL;DR: Current knowledge of the complex biology of the endocrine FGFs is discussed and how this may be harnessed therapeutically is assessed.
Journal ArticleDOI
FGF21 as Modulator of Metabolism in Health and Disease.
TL;DR: The recent findings that identify FG21 as beneficial and/or detrimental cytokine interacting as an autocrine or endocrine in order to modulate cellular function, metabolism, and senescence are discussed.
Journal ArticleDOI
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
TL;DR: This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and humans that have to be considered before translation from bench to bedside can be successful.
Journal ArticleDOI
FGF21 and the late adaptive response to starvation in humans
Pouneh K. Fazeli,Mingyue Lun,Soo Min Kim,Miriam A. Bredella,Spenser M Wright,Yang Zhang,Hang Lee,Ciprian Catana,Anne Klibanski,Parth Patwari,Matthew L. Steinhauser +10 more
TL;DR: FGF21 is established as a fasting-induced hormone in humans and FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown, and a longitudinal analysis of biologically relevant variables identified serum transaminases--markers of tissue breakdown--as predictors of FGF 21.
Journal ArticleDOI
Fibroblast Growth Factor Signaling in Metabolic Regulation
Vera J. M. Nies,Gencer Sancar,Weilin Liu,Tim van Zutphen,Dicky Struik,Ruth T. Yu,Annette R. Atkins,Ronald M. Evans,Johan W. Jonker,Michael Downes +9 more
TL;DR: The goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions.
References
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Journal ArticleDOI
Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting
Sander Kersten,Josiane Seydoux,Jeffrey M. Peters,Frank J. Gonzalez,Béatrice Desvergne,Walter Wahli +5 more
TL;DR: It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPAR α mRNA is induced during fasting in wildtype mice, indicating that PPARα plays a pivotal role in the management of energy stores during fasting.
Journal ArticleDOI
Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21
Takeshi Inagaki,Paul A. Dutchak,Guixiang Zhao,Xunshan Ding,Laurent Gautron,Vinay Parameswara,Yong Li,Regina Goetz,Moosa Mohammadi,Victoria Esser,Joel K. Elmquist,Robert D. Gerard,Shawn C. Burgess,Robert E. Hammer,David J. Mangelsdorf,Steven A. Kliewer +15 more
TL;DR: These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.
Journal ArticleDOI
Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States
Michael K. Badman,Pavlos Pissios,Adam R. Kennedy,George Koukos,Jeffrey S. Flier,Eleftheria Maratos-Flier +5 more
TL;DR: Induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD, and a physiological role for this hepatic hormone is identified.
Journal ArticleDOI
Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans
Xinmei Zhang,Dennis C.Y. Yeung,Michal Karpisek,David Stejskal,Zhiguang Zhou,Feng Liu,Rachel L.C. Wong,Wing Sun Chow,Annette W.K. Tso,Karen S.L. Lam,Aimin Xu +10 more
TL;DR: FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans and the paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF 21, warrants further investigation.
Journal ArticleDOI
Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21
Hiroshi Kurosu,Mihwa Choi,Yasushi Ogawa,Addie S. Dickson,Regina Goetz,Anna V. Eliseenkova,Moosa Mohammadi,Kevin P. Rosenblatt,Steven A. Kliewer,Makoto Kuro-o +9 more
TL;DR: It is demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively.
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