Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance
Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance
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DOI：
10.1210/en.2008-0655
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Bordin, Silvana
中科院分区：
文献类型：
--
作者：
Caperuto, Luciana Chagas;Anhe, Gabriel Forato;Bordin, Silvana
骨形态发生蛋白9（BMP-9）是TGF-β超家族的一员，主要在非实质肝细胞中表达，已被证明可改善糖尿病小鼠的葡萄糖稳态。沿着这种治疗效果，BMP-9被提议作为肝胰岛素增敏物质（HISS）的候选物。BMP-9是否在葡萄糖稳态中发挥生理作用仍不清楚。在本研究中，我们发现，BMP-9的表达和加工严重减少胰岛素抵抗大鼠的肝脏。BMP-9的表达和加工直接刺激原位暴露的肝脏葡萄糖和胰岛素的组合和口服葡萄糖在过夜禁食大鼠。此外，长期禁食（72小时）废除再喂养诱导的BMP-9的表达和加工。先前暴露于地塞米松，一种已知的胰岛素抵抗诱导剂，减少了由胰岛素和葡萄糖的组合刺激的BMP-9加工。最后，我们表明，中和BMP-9与抗BMP-9抗体诱导葡萄糖耐受不良和胰岛素抵抗在12小时禁食大鼠。总之，本研究结果表明，BMP-9在正常大鼠的葡萄糖稳态的控制中起着重要的作用。此外，BMP-9以HIS样方式表达和加工，其在胰岛素抵抗的存在下受损。BMP-9根据进食状态和致糖尿病因素的存在进行调节，这加强了BMP-9可能在葡萄糖稳态生理学中发挥HISS作用的假设。（内分泌学149：6326-6335，2008）
Bone morphogenetic protein 9 (BMP-9), a member of the TGF-beta superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance ( HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting ( 72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology. ( Endocrinology 149: 6326-6335, 2008)