Insulin suppresses the production of fibroblast growth factor 23 (FGF23)
Insulin suppresses the production of fibroblast growth factor 23 (FGF23)
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DOI：
10.1073/pnas.1800160115
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发表时间：
2018-05-29
影响因子：
11.1
通讯作者：
Foeller, Michael
中科院分区：
文献类型：
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作者：
Baer, Ludmilla;Feger, Martina;Foeller, Michael
成纤维细胞生长因子23(FGF23)由骨细胞产生，调节肾脏磷酸盐和维生素D代谢，并导致左心室肥厚。FGF23缺乏会导致快速衰老，而高水平的血浆FGF23在几种疾病中被发现，包括肾脏或心血管疾病。FGF23产生的调节因素包括甲状旁腺激素(PTH)、骨化三醇、饮食中的磷酸盐和炎症。我们报道胰岛素和胰岛素样生长因子1(IGF1)是FGF23产生的负调控因子。在UMR106成骨样细胞中，胰岛素和IGF1通过PI3K/PKB/Akt信号通路抑制转录因子叉头盒蛋白O1(FOXO1)，从而下调FGF23的生成。胰岛素缺乏导致小鼠血清FGF23浓度激增，这一现象可被注射胰岛素逆转。在女性中，口服葡萄糖负荷后，FGF23血浆浓度和血浆胰岛素水平的升高之间存在高度显著的负相关。我们的结果提供了强有力的证据，证明依赖于胰岛素/IGF1的PI3K/PKB/Akt/FOXO1信号通路在体外以及在小鼠和人类中都能有效地抑制FGF23的产生。
Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.