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.
Highlights
The mechanism whereby the circadian clock regulates phosphate metabolism remains elusive
Because it is well known that food consumption reaches highest at the beginning of dark phase (DP) in mice fed ad libitum (AL), we speculated that skeletal Fgf23 expression was regulated by the food consumption in a manner involving the circadian clock system
Because it is unclear whether skeletal tissue is entrained by nutrient availability despite the fact that food intake is a strong zeitgeber in peripheral tissues such as liver, we examined the circadian expression profiles of genes involved in daily oscillations in the femur
Summary
The mechanism whereby the circadian clock regulates phosphate metabolism remains elusive. The mechanism of circadian regulation of Fgf induction by ISO in vivo was partly explained by the suppressive effect of Cryptochrome (Cry1) on ISO signaling These results indicate that the regulation of skeletal Fgf 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. We demonstrated that stimulation with a -adrenergic receptor agonist induced Fgf expression, which was suppressed by the overexpression of Cry1 These results underline the important roles of the circadian clock system in the regulation of phosphate metabolism
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