BMP9 Action in the Hypothalamus Suppresses Hepatic Glucose Production Through a Central PI3K/Akt /mTOR Pathway

Background: Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) superfamily of proteins. BMP7 has been reported to traverse obesity and regulates appetite in the hypothalamus. However, whether central BMP9 regulates glucose metabolism and insulin sensitivity remains unclear. In this study, we focused on the impacts of central BMP-9 signaling and possible route of transmission. Methods: We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) or adenovirus encoding enhanced green fluorescence protein (Ad-GFP) into cerebral ventricle of mice. Then metabolic analyses, hyperinsulinemic-euglycemic clamp (HEC) and analysis of PIP3 formation were fulfilled. Real-time PCR and Western blot were performed to investigate potential pathway. Findings: We exhibited that hypothalamic BMP9 expression was downregulated in obese or insulin resistance (IR) mice. Overexpression of BMP9 in the hypothalamus reduced food intake, body weight, blood glucose, and elevated energy expenditure in high fat diet (HFD)-fed mice. Importantly, central treatment of BMP9 improved hepatic IR and inhibited hepatic glucose production (HGP) in mice fed with HFD. The increased hepatic insulin sensitivity and the related metabolic impacts by central BMP9 were blocked by ICV rapamycin injection (an inhibitor of the mTOR signaling). In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor (InsR)/PI3K/Akt kinase pathway in hypothalamus. Interpretation: This study provided insight into the potential mechanism by which central BMP9 ameliorates glucose metabolism and IR by promoting the ability insulin to activate the mTOR/PI3K/Akt signaling in the hypothalamus.   Funding Statement: This work was supported by grants from National Natural Science Foundation (No:81873658, 81670755), the Natural Science Foundation Project of CQ (No. cstc2015jcyjA10084 and cstc2013 jcyjA 10067) and the Science and Technology Key Program of Health Bureau of Chongqing (2015ZDXM038). Declaration of Interests: The authors have no conflict of interests to declare. Ethics Approval Statement: In the study, all kinds of treatments for mice were strictly carried out in accordance with the administrative animal management method of Chongqing Medical University, and at the same time, they met the relevant regulations of the Ethics Society of Chongqing Medical University.