The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China.
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
J Endocrinol. 2021 Feb;248(2):221-235. doi: 10.1530/JOE-19-0591.
Bone morphogenetic proteins (BMPs) are secreted ligands that belong to the transforming growth factor-β (TGF-β) superfamily. BMP7 has been reported to play a role in reversing obesity and regulating appetite in the hypothalamus. Whether BMP9 plays a central role in regulating glucose metabolism and insulin sensitivity remains unclear. Here, we investigated the impact of central BMP9 signaling and possible route of transmission. We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) into the cerebral ventricle of mice. Metabolic analysis, hyperinsulinemic-euglycemic clamp test, and analysis of phosphatidylinositol 3,4,5-trisphosphate (PIP3) formation were then performed. Real-time PCR and Western blotting were performed to detect gene expression and potential pathways involved. We found that hypothalamic BMP9 expression was downregulated in obese and insulin-resistant mice. Overexpression of BMP9 in the mediobasal hypothalamus reduced food intake, body weight, and blood glucose level, and elevated the energy expenditure in high-fat diet (HFD)-fed mice. Importantly, central treatment with BMP9 improved hepatic insulin resistance (IR) and inhibited hepatic glucose production in HFD-fed mice. ICV BMP9-induced increase in hepatic insulin sensitivity and related metabolic effects were blocked by ICV injection of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling. In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor/phosphoinositide 3-kinase (PI3K)/Akt pathway in the hypothalamus. Thus, this study provides insights into the potential mechanism by which central BMP9 ameliorates hepatic glucose metabolism and IR via activating the mTOR/PI3K/Akt pathway in the hypothalamus.
骨形态发生蛋白（BMPs）是属于转化生长因子-β（TGF-β）超家族的分泌配体。已有报道称，BMP7 在逆转肥胖和调节下丘脑食欲方面发挥作用。BMP9 是否在调节葡萄糖代谢和胰岛素敏感性方面发挥中枢作用尚不清楚。在这里，我们研究了中枢 BMP9 信号转导及其可能的传递途径。我们对小鼠进行了侧脑室（ICV）手术，并将表达 BMP9 的腺病毒（Ad-BMP9）注入脑室。然后进行代谢分析、高胰岛素-正常血糖钳夹试验和磷脂酰肌醇 3,4,5-三磷酸（PIP3）形成分析。进行实时 PCR 和 Western blot 以检测涉及的基因表达和潜在途径。我们发现肥胖和胰岛素抵抗小鼠下丘脑 BMP9 表达下调。在中脑基底部过度表达 BMP9 可减少高脂肪饮食（HFD）喂养小鼠的食物摄入、体重和血糖水平，并增加能量消耗。重要的是，中枢给予 BMP9 可改善 HFD 喂养小鼠的肝胰岛素抵抗（IR）并抑制肝葡萄糖生成。ICV BMP9 诱导的肝胰岛素敏感性增加和相关代谢效应被哺乳动物雷帕霉素靶蛋白（mTOR）信号抑制剂 rapamycin 的 ICV 注射阻断。此外，ICV BMP9 促进了胰岛素在下丘脑激活胰岛素受体/磷酸肌醇 3-激酶（PI3K）/Akt 途径的能力。因此，本研究提供了关于中枢 BMP9 通过激活下丘脑 mTOR/PI3K/Akt 途径改善肝葡萄糖代谢和 IR 的潜在机制的见解。
