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Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

Author

Listed:
  • Chuanxin Zhong

    (School of Chinese Medicine, Hong Kong Baptist University
    Southern University of Science and Technology, Shenzhen
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University)

  • Nanxi Li

    (School of Chinese Medicine, Hong Kong Baptist University
    School of Chinese Medicine, Hong Kong Baptist University)

  • Shengzheng Wang

    (School of Pharmacy, Fourth Military Medical University)

  • Dijie Li

    (School of Chinese Medicine, Hong Kong Baptist University
    College of Life Sciences, Guangxi Normal University)

  • Zhihua Yang

    (The Second Affiliated Hospital of Guangzhou University of Chinese Medicine)

  • Lin Du

    (The First Affiliated Hospital of Shantou University Medical College)

  • Guangxin Huang

    (The Third Affiliated Hospital of Southern Medical University, The Third School of Clinical Medicine, Southern Medical University)

  • Haitian Li

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Wing Sze Yeung

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Shan He

    (Southern University of Science and Technology, Shenzhen)

  • Shuting Ma

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Zhuqian Wang

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Hewen Jiang

    (Faculty of Medicine, The Chinese University of Hong Kong)

  • Huarui Zhang

    (Faculty of Medicine, The Chinese University of Hong Kong)

  • Zhanghao Li

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Xiaoxin Wen

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Song Xue

    (Peking University Shenzhen Hospital)

  • Xiaohui Tao

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Haorui Li

    (The First Affiliated Hospital of Shantou University Medical College)

  • Duoli Xie

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Yihao Zhang

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Zefeng Chen

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Junqin Wang

    (Southern University of Science and Technology, Shenzhen)

  • Jianfeng Yan

    (Southern University of Science and Technology, Shenzhen)

  • Zhengming Liang

    (School of Chinese Medicine, Hong Kong Baptist University)

  • Zongkang Zhang

    (Faculty of Medicine, The Chinese University of Hong Kong)

  • Zhigang Zhong

    (The First Affiliated Hospital of Shantou University Medical College)

  • Zeting Wu

    (The First Affiliated Hospital of Shantou University Medical College)

  • Chao Wan

    (Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong)

  • Chao Liang

    (Southern University of Science and Technology)

  • Luyao Wang

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University)

  • Sifan Yu

    (Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    Faculty of Medicine, The Chinese University of Hong Kong)

  • Yuan Ma

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery)

  • Yuanyuan Yu

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University)

  • Fangfei Li

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University)

  • Yang Chen

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Baoting Zhang

    (Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    Faculty of Medicine, The Chinese University of Hong Kong)

  • Aiping Lyu

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research)

  • Fuzeng Ren

    (Southern University of Science and Technology, Shenzhen)

  • Hong Zhou

    (ANZAC Research Institute, The University of Sydney)

  • Jin Liu

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University
    Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Ge Zhang

    (School of Chinese Medicine, Hong Kong Baptist University
    Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery
    School of Chinese Medicine, Hong Kong Baptist University)

Abstract

Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Suggested Citation

  • Chuanxin Zhong & Nanxi Li & Shengzheng Wang & Dijie Li & Zhihua Yang & Lin Du & Guangxin Huang & Haitian Li & Wing Sze Yeung & Shan He & Shuting Ma & Zhuqian Wang & Hewen Jiang & Huarui Zhang & Zhangh, 2024. "Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52965-4
    DOI: 10.1038/s41467-024-52965-4
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    as
    1. Jing Li & Jun Song & Yekaterina Y. Zaytseva & Yajuan Liu & Piotr Rychahou & Kai Jiang & Marlene E. Starr & Ji Tae Kim & Jennifer W. Harris & Frederique B. Yiannikouris & Wendy S. Katz & Peter M. Nilss, 2016. "An obligatory role for neurotensin in high-fat-diet-induced obesity," Nature, Nature, vol. 533(7603), pages 411-415, May.
    2. Giorgio Caratti & Ulrich Stifel & Bozhena Caratti & Ali J. M. Jamil & Kyoung-Jin Chung & Michael Kiehntopf & Markus H. Gräler & Matthias Blüher & Alexander Rauch & Jan P. Tuckermann, 2023. "Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Defang Li & Jin Liu & Baosheng Guo & Chao Liang & Lei Dang & Cheng Lu & Xiaojuan He & Hilda Yeuk-Siu Cheung & Liang Xu & Changwei Lu & Bing He & Biao Liu & Atik Badshah Shaikh & Fangfei Li & Luyao Wan, 2016. "Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation," Nature Communications, Nature, vol. 7(1), pages 1-16, April.
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