Hypothalamic BMP9 suppresses glucose production by central PI3K/Akt/mTOR pathway

in Journal of Endocrinology
Authors:
Yirui He 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

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Cheng Zhang The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China

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Yong Luo The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China

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Jinhua Chen Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

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Mengliu Yang The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China

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https://orcid.org/0000-0002-6458-6747
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Ling Li Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China

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https://orcid.org/0000-0002-0087-3034
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Harvest F Gu Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden

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Gangyi Yang 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

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Xianxiang Zhang The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China

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Correspondence should be addressed to G Yang or X Zhang: gangyiyang@hospital.cqmu.edu.cn or xianxiangzhangcqsx@126.com

*(Y He and C Zhang contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-19-0591
Volume/Issue:
Volume 248: Issue 2
Article Type:
Research Article
Page Range:
221–235
Online Publication Date:
Feb 2021
Copyright:
© 2021 Society for Endocrinology 2021
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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.

Supplementary Materials

    • Fig. S1 Identification of BMP9 antibody.
    • Fig. S2 BMP9 mRNA expression in kidney and hypothalamus. Data are means ± SE (n = 3/group). **p < 0.01 vs. kidney.
    • Fig. S3 Entire membrane for BMP9 western blot. (A) Entire membrane from Figure 1B. (B) Entire membrane from Figure 2A.
    • Fig. S4 Central BMP9 protects mice from HFD-induced obesity and insulin resistance. (A) Body composition, expressed as % total body weight. (B) GTT in HFD mice treated with Ad-BMP9 or Ad-GFP for three days. Data are means ± SE (n = 5/group). *p < 0.05, **p < 0.01 vs. Ad-GFP.
    • Fig. S5 Time course of blood glucose and GIR changes during the steady-state of HEC. (A) Blood glucose. (B) GIR. NCD, normal chow diet; HFD, high-fat diet. GIR, glucose infusion rate. Data are expressed as mean ± SE (n = 5/group).
    • Fig. S6 Hepatic innervation is required for hypothalamic BMP9 to regulate glucose metabolism. 8-week-old male C57BL/6J were fed an HFD for 12 weeks. Seven days before the HECs, mice were performed the HVG or SHAM and received ICV injection of Ad-BMP9 or Ad-GFP. (A) Body weight and food intake in mice with SHAM or HVG. (B) During the GTT, blood glucose, and AUC. (C) During the ITT, blood glucose, and AUC. AUC, the area under the curve for glucose; HVG, hepatic branch vagotomy; SHAM, sham-operation. Data are means ± SE (n = 5/group). *p < 0.05, **p < 0.01 vs. Ad-GFP.
    • Table S1. The specific primers sequence used for RT-PCR analysis
    • Table S2. Biochemical parameters in experimental animals
    • Table S3. Biochemical parameters during the hyperinsulinemic clamp studies

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
15
Article Type:
Research Article
Received Date:
09 Nov 2020
Accepted Date:
16 Dec 2020
Print Publication Date:
01 Feb 2021
Online Publication Date:
Feb 2021
Keywords:
BMP9; glucose metabolism; hypothalamus; insulin resistance; mTOR

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