title: FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting.
abstract: Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Qingning
authors.initials: Q
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha, Qatar.
authors.forename: Chris R
authors.initials: CR
authors.lastname: Triggle
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha, Qatar.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China amxu@hku.hk ksllam@hku.hk.
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China amxu@hku.hk ksllam@hku.hk.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005215:Fasting / Q000378:metabolism* / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005943:Gluconeogenesis / Q000235:genetics* / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005947:Glucose