title: Sympathetic activation induces skeletal Fgf23 expression in a circadian rhythm-dependent manner.
abstract: The circadian clock network is well known to link food intake and metabolic outputs. Phosphorus is a pivotal nutritional factor involved in energy and skeletal metabolisms and possesses a circadian profile in the circulation; however, the precise mechanisms whereby phosphate metabolism is regulated by the circadian clock network remain largely unknown. Because sympathetic tone, which displays a circadian profile, is activated by food intake, we tested the hypothesis that phosphate metabolism was regulated by the circadian clock network through the modification of food intake-associated sympathetic activation. Skeletal Fgf23 expression showed higher expression during the dark phase (DP) associated with elevated circulating FGF23 levels and enhanced phosphate excretion in the urine. The peaks in skeletal Fgf23 expression and urine epinephrine levels, a marker for sympathetic tone, shifted from DP to the light phase (LP) when mice were fed during LP. Interestingly, β-adrenergic agonist, isoproterenol (ISO), induced skeletal Fgf23 expression when administered at ZT12, but this was not observed in Bmal1-deficient mice. In vitro reporter assays revealed that ISO trans-activated Fgf23 promoter through a cAMP responsive element in osteoblastic UMR-106 cells. The mechanism of circadian regulation of Fgf23 induction by ISO in vivo was partly explained by the suppressive effect of Cryptochrome1 (Cry1) on ISO signaling. These results indicate that the regulation of skeletal Fgf23 expression by sympathetic activity is dependent on the circadian clock system and may shed light on new regulatory networks of FGF23 that could be important for understanding the physiology of phosphate metabolism.
authors.affiliation: From the Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawai
authors.forename: Saori
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimba
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D004837:Epinephrine / Q000652:urine; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010710:Phosphates / Q000652:urine; D020218:Response Elements / Q000502:physiology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism*; D013566:Sympathomimetics / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D013566:Sympathomimetics; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D007545:Isoproterenol; D004837:Epinephrine
keywords: Bone; Circadian Rhythms; Cryptochrome1; FGF23; Fibroblast Growth Factor (FGF); Nerve; Parathyroid Hormone; Phosphate Metabolism; Sympathetic Activity