Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
Department of Physiology and Molecular Biology, Bangladesh University of Health Sciences, Dhaka-1216, Bangladesh.
Proc Natl Acad Sci U S A. 2018 May 29;115(22):5804-5809. doi: 10.1073/pnas.1800160115. Epub 2018 May 14.
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/IGF1-dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.
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，而几种疾病（包括肾脏或心血管疾病）患者的血浆 FGF23 水平较高。FGF23 产生的调节因子包括甲状旁腺激素（PTH）、骨化三醇、饮食磷酸盐和炎症。我们报告称，胰岛素和胰岛素样生长因子 1（IGF1）是 FGF23 产生的负调节因子。在 UMR106 成骨样细胞中，胰岛素和 IGF1 通过磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（PKB）/Akt 信号通路抑制叉头框蛋白 O1（FOXO1）转录因子，从而下调 FGF23 的产生。胰岛素缺乏会导致小鼠血清 FGF23 浓度激增，而给予胰岛素可逆转这种情况。在女性中，发现 FGF23 血浆浓度与口服葡萄糖负荷后血浆胰岛素水平升高之间存在高度显著的负相关。我们的研究结果提供了有力的证据，表明胰岛素/IGF1 依赖性 PI3K/PKB/Akt/FOXO1 信号通路是体外以及小鼠和人类中 FGF23 产生的强大抑制剂。
